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Past Issues
Volume 19, number 5/6
May/June 2005
Protecting Against HPV
Condom use can help stop human papillomavirus (HPV)
and now there are vaccines on the way. Will they
be allowed to work?
A Lame Duck, a Dark Horse,
and a Goat.
Three experimental HIV drugs take three different paths
Aptivus® in the Hot Seat
Discussions from the FDA advisory committee meeting on tipranavir
The View from Keystone
Gareth Hardy finds optimism in the Rockies over new immunology and vaccine research
Playing God in Kathmandu
Rajiv Kafle outlines the responsibilities
The Invisible IDU
Daniel Raymond on the U.S. response to the epidemic in injection drug users
Protecting Against HPV
The Next Battleground?
By David Gilden
Human papillomavirus (HPV) is many things to many people. As an infection of the
skin, some varieties of HPV can cause annoying warts on the hands or feet, while other
varieties of HPV infect the mucosa of the genitals and can cause warts — or
worse — there.
There may be more than 100 kinds of HPV variants, with a few strongly linked
to the development of cervical and anal cancer. Because the transmission of these
worrisome kinds of HPV are associated with sex, the fight against the virus is
becoming increasingly fraught with all of the fears, myths and misinformation that
now accompanies any public health response to sexual issues in the United States.
With two new vaccines against HPV on the horizon, there are emerging concerns that
these weapons may not be effectively deployed due to moral and political objections.
HPV infection is the most common sexually transmitted disease in the United States.
Over 5 million cases are thought to occur each year, with half of all women between
the ages 18 to 22 having vaginal infections at some point. The anal infection rate
in young gay men is higher still. Infection occurs through skin-to-skin contact —
including areas not covered by condoms — and warts need not be present for
transmission to occur. Most infections are transient and are cleared by the
immune system. Of the 40 or so types of HPV that infect the genital and anal
regions, those that cause genital warts are deemed "low-risk" whereas those
linked to cancer of the cervix or anus are termed "high risk." Types 16 and
18 are the most common high-risk varieties. Most HIV-negative people —
and 90 percent of women — clear HPV infections within two years, but
infections with types 16 and 18 seem to last longer. Studies have consistently
found that persistent infection with varieties such as 16 and 18 are a necessary
precondition for the development of precancerous lesions. Those who clear the
virus are out of danger.
Although there is no treatment for chronic HPV infection, control of the
associated anal and cervical cancers is fairly straightforward. Even so,
there are about 5,000 U.S. deaths a year from such cancers and HPV infections
may be more common and more difficult to treat in people with HIV.
Recently, the pharmaceutical manufacturers Merck and GlaxoSmithKline
(GSK) each reported excellent results from preliminary trials of new
vaccines against HPV. Merck expects to file for FDA marketing approval
in the fall of 2005 and GSK in early 2006. Because of the ubiquity of
the virus and the deadly consequence of infection in some people, a
preventative vaccine for HPV could have significant public health
benefits. Since active HPV infection may also increase the risk for
acquiring HIV there has also been much speculation about the potential
impact of these vaccines on HIV transmission rates.
Abstinence Above All Else
In their battle to implement abstinence-until-marriage as official U.S.
health policy, HPV has become a favorite cause of religious conservatives
because of its cancer-causing potential, its widespread nature, and because
it allows them to raise questions about the value of condoms in protecting
against disease. These dangers are exaggerated because most HPV infections
are largely transitory in nature, but facts have not been at the center
of this campaign.
"Abstinence is the best way to prevent HPV... Giving the HPV vaccine
to young women could be potentially harmful, because they may see it as
a license to engage in premarital sex," Bridget Maher, policy analyst for
the Family Research Council (FRC) told New Scientist magazine this spring.
Is it possible that an intervention as practical and necessary as a vaccine
to prevent HPV could be derailed by such logic? Many fear that in the current
political climate, it could.
Condoms as Protection
New studies presented this summer found that condom use does indeed correlate
with protection against HPV. In the most strictly designed study yet of college
women who were just beginning an active sexual life, self-reported 100 percent
condom use resulted in a 70 percent reduction in genital HPV infections when
compared with condom use in less than 5 percent of sexual encounters. Prior
studies were more equivocal, and abstinence promoters like FRC frequently cite
them. The older studies had severe limitations, however, as they included large
numbers of women with past HPV infection. "Those studies did not cover the right
population. It's hard to find women who haven't been infected by HPV already,
and they weren't looking specifically at condoms," commented Laura Koutsky,
the new study's senior author. Women with past exposure to HPV strains already
have antibodies to protect them against those strains.
Reflecting Koutsky's concerns, another recent condom study looked at sexually
experienced HIV-negative gay men and found that 60 percent had active HPV infections.
In this study, those who always used condoms during receptive anal intercourse had
one-third fewer new HPV infections than with those who used condoms less than 70
percent of the time.
The vaccine trials have run up against this same problem — the universality
of HPV — when trying to gauge the vaccines' effect in men who have sex with men
(MSM). Koutsky said, "You need to recruit never-infected gay men, but most MSM will
already be infected so it's a hard study to do. Young gay men have many more sex partners
than young women at the same age [and therefore more past HPV]. Limiting MSM to those
with few sex partners would make it even harder to recruit."
Market Strategy Shapes the Vaccine
Merck's and GSK's responses to the technical and political challenges diverge
considerably, and the contents of their vaccines — even their names —
reflect the different positions.
GSK's vaccine, Cervarix, includes only HPV strains 16 and 18, which are responsible
for 70 percent of cervical malignancies. The company plans to market the vaccine exclusively
to women, as a cancer prevention agent. GSK claims that it would not be cost-effective to
also vaccinate men and has conducted no studies with males or on anal cancer.
In an e-mail, GSK spokeswomen Amy Pollack told community groups, "Because cervical
cancer takes many years to develop and remains asymptomatic for many years, it is easier
to turn the question of introduction in girls into a hypothetical or political debate
about adolescent sexuality. We will need your support in staying focused on drawing
attention to and advocating for the real problem of cervical cancer."
Merck's version, Gardasil, includes HPV 6 and 11 in addition to 16 and 18. Strains
6 and 11 are implicated in 90 percent of genital warts. "The goal was, from a public
health perspective, to protect against cancer and reduce the overall HPV health care
burden," said Kelly Dougherty of Merck.
Both vaccines are three-dose affairs made up of noninfectious "virus-like
particles," noninfectious synthetic shells made up of core protein from the
targeted HPV strains. The GSK vaccine's main selling point is its proprietary
adjuvant, "AS04," designed to trigger a quicker and stronger immune response.
The response is said to be more durable, too, although the difference between
an AS04-containing vaccine and one with the traditional aluminum salt adjuvant
diminishes over time. In a phase II placebo-controlled trial, 721 women 15
to 25 years old completed the vaccine protocol. A significant reduction in
new HPV 16/18 infections was seen in cervical and vaginal tissues (74% reduction
compared to placebo after 27 months). In that period, the protection against
persistent infection (at least six months duration) was 100 percent. GSK also
recently reported evidence that its vaccine conferred 75 percent cross-protection
against recurrent infection in several secondary oncogenic HPV types (31, 45
and 52). This would imply a possible further decline in overall cervical cancer
rates among vaccine recipients.
Follow-up is continuing in the GSK phase II trial while four phase III
trials have commenced. The phase III trials include a total of 36,000 women
ranging from teenaged to 55 years old, with the vast majority 15 to 25.
Merck has reported similar compelling results for its quadrivalent
vaccine. A phase II trial followed 478 women aged 16 to 23 for 36 months.
The vaccine recipients' reduction of persistent infection was 89 percent
overall compared with those who received the placebo. Protection against
persistent HPV 16 was 86 percent; the vaccine conferred 89 percent protection
against type 18. Merck has also reported that antibody response to the vaccine
is stronger in 10 to 15 year-old males and females compared with 16 to 23
year-old females. There has always been an obvious need to vaccinate
adolescents before they become sexually active, and these results strengthen
the rationale for vaccinating younger individuals.
Merck has an ongoing study in 4,000 young men that contains an anal
cancer endpoint as well as measuring heterosexual transmission. It is
specifically including men who have sex with men. A study sponsored by
the National Institutes of Health is evaluating response to the vaccine
in preteen boys and girls infected with HIV. It provides an opportunity
to evaluate its preventive potential in an HIV-positive cohort that has
yet to be exposed to HPV. Overall, Merck's phase III trials have enrolled
25,000 persons, mostly young women. Women aged 25 to 45 have also been
recruited in addition to young men. Later this year, Merck will go to
the FDA with phase III data on efficacy in women (as judged by rates
of persistent infection and advanced pre-cancerous lesions) plus
immunogenicity (antibody response) in male and female adolescents.
More than Cervical Cancer
A major compelling factor for the companies is that these vaccines promise
to be marketing bonanza — with each three-dose course expected to
cost in the neighborhood of $300. Merck, for example, is planning to switch
its old Vioxx sales network to Gardasil after FDA approval. Both companies
will initially market the vaccines to young women.
Merck and GSK claim confidence that the FDA will recognize the medical
consensus that vaccines will be a great help in controlling HPV-associated
disease. Merck's Daugherty said, "We are confident that the regulatory
agencies and everyone will want to use all the tools available to control
HPV. Everyone we speak to is eager."
FDA approval is just the beginning to achieving broad public access.
Guidelines from the Centers for Disease Control and Prevention (CDC) will
determine which patients Medicaid and insurance companies will cover for
this unprecedentedly expensive vaccine. A big battle may emerge over whether
the guidelines ask schools to require the vaccine. This issue could be
fought in community after community, where religious conservatives hold
great sway.
The population most in need of the vaccine includes young people before
sexual debut and those with high HIV risk. Gay and questioning teenagers
are at the intersection of these criteria. Adolescents may not have the
knowledge or means to obtain the vaccines on their own. Company preapproval
presentations, meanwhile, already are replete with pictures of virginal,
middle class young women. College students will certainly benefit from
immunization, but the public health benefits will be greatly circumscribed
if availability is limited to affluent adult women. Without help in
obtaining access, the younger, less empowered teens could prove the weak
link in eliminating HPV and its associated malignancies.
HPV by Itself and with HIV
Chronic HPV is, in principle, a manageable disease. Cellular changes can
be monitored via cervical and anal Pap smears. Early-stage pre-cancerous and
cancerous tumors can be excised before any malignancy has a chance to metastasize
into the pelvic region, where they can prove disastrous. The United States,
where regular cervical Pap screening is common, still records 14,000 cases
of cervical cancer per year, including 4,000 deaths. For the world as a whole,
there are nearly 300,000 cervical cancer deaths annually. Anal Pap smears are
not usually preformed in the U.S. or elsewhere outside of a few medical practices
that serve large numbers of gay men. The rate of anal cancer in gay men before
the onset of the HIV epidemic is frequently compared with that of cervical
cancer in women during the pre-Pap smear era. Yet because the U.S. gay male
population is much smaller than that of all American women, the total anal
cancer caseload is low compared to that of cervical cancer — about
4,000 new cases in men and women and 700 deaths per year according to American
Cancer Society estimates.
People with HIV have a considerably harder time eliminating HPV and a
much higher prevalence of precancerous cervical and anal lesions (HSIL,
or high-grade squamous epithelial lesions). A 1998 study found that persons
with HIV had anal cancer rates 15 to 30 times that of the general population
depending on the stage of HIV disease. There is even one report of HSIL in
18 percent of 117 HIV-positive men who denied ever engaging in receptive anal
intercourse. By comparison, a recent study of HIV-negative MSM found a 5
percent rate of HSIL. Unfortunately, administration of antiretroviral therapy
has proved to have at best modest effect on reversing pre-cancerous or cancerous
lesions.
HPV is related to HIV transmission, too. It is widely thought that active
infection — and certainly the lesions associated with such infection
— makes people vulnerable to acquiring HIV. HPV also increases genital
HIV levels, and this would be another way HPV promotes HIV transmission. Still,
there are little hard data on the relationship between HPV and HIV acquisition.
A new study to be presented at the 3rd International HIV Pathogenesis and Treatment
Conference does indicate such a relationship. Joel Palefsky, the study's senior
author notes, "I would say that the evidence is still very preliminary but
strongly suggests the need for more work in this area. If confirmed, it would
be very important indeed." The possibility of HIV transmission would be a major
additional reason for male use of the HPV vaccine, even in the absence of
specific studies.
– DG |
A Lame Duck, a Dark Horse, and a Goat
By Bob Huff
Tipranavir
Tipranavir (Aptivus) is a protease inhibitor (PI) with activity against HIV
that is resistant to most available PIs. Apitvus was approved for sale in the
United States on June 22, 2005. The drug is indicated for the treatment of HIV
infection in combination with other antiretroviral (ARV) drugs in adults with
unsuppressed virus and extensive experience with protease inhibitors or evidence
of resistance to multiple PIs. The dose of Aptivus is 500mg (two 250mg capsules)
taken twice daily. The drug must be co-administered with 200mg of ritonavir
(Norvir) as a pharmacokinetic booster.
Twenty-four week experience in two Phase III trials in highly treatment
experienced patients demonstrated that the best antiviral response was obtained
when Aptivus was used in combination with at least one other ARV with activity
against the patient's virus. In most individuals requiring so-called salvage
therapy, this means Aptivus will be combined with Fuzeon to achieve the optimal
effect.
The sprawling package insert supplied with Aptivus runs to five feet of
tiny-type information about drug-drug interactions and toxicity warnings. But
the main warning is placed in a box at the top of the label: "Aptivus co-administered
with 200mg ritonavir has been associated with reports of clinical hepatitis and
hepatic decompensation including some fatalities. Extra vigilance is warranted
in patients with chronic hepatitis B or hepatitis C coinfection, as these patients
have an increased risk of hepatotoxiticity."
While this warning singles out those with hepatitis, hepatic injury also
occurred to individuals in the clinical trials who had no prior evidence of
liver problems. The bottom line for this drug is, if you need it, you need
it; and it may well save your life. But keep an eye on your liver.
Tipranavir originated in a cardiovascular research lab at Pharmacia Upjohn
(PU) that had been looking for renin inhibitors in the 1980s. Renin is an
aspartyl protease, like HIV protease, so many workers in that field segued
into HIV research projects in the 1990s. Straight out of Kalamazoo, PNU-140690
first appeared in the scientific press in 1996. By 1997 it was dubbed tipranavir
and put into a human body. But PU stumbled through their initial clinical
development program and when Boehringer Ingelheim (BI) acquired rights to
the drug in 2000, they soon realized that much of the basic development work
needed to be done over.
Tipranavir would have been right on time in 2001. Resistance was rampant
and people were accustomed to hard-to-tolerate PIs. But as BI's development
program dragged on, the field passed them by as boosted PIs and simpler regimens
made therapy less burdensome. Yet salvage patients were, and still are, being
produced everyday and, while not the sexiest market, they represent the most
pressing unmet medical need in HIV.
Aptivus might be a lifesaver for those who need it and can stand it, but
it's certainly not for everybody. With this drug we now see a clear divergence
in HIV therapy. Treating drug resistant HIV — especially in persons with
advanced AIDS — is a complicated and not always successful business. Like
treating cancer, it is a job for a specialist. Meanwhile, treating wild type
HIV — when it has not progressed too far along — is becoming more
like treating high blood pressure or cholesterol, where therapy is guided by
the test numbers. Still, if you don't get it right, there is a high probability
that you can cross over into the other group.
Not coincidentally, the cost of the salvage drugs are increasingly lining
up with the cost of cancer therapies. While a simple Sustiva-based regimen might
run $15,000 a year, a salvage regimen that includes tipranavir and Fuzeon could
be pushing $50,000 per year. Although the price of Aptivus came in significantly
higher than the price for Reyataz, the last PI to be approved, once you add in
the cost of the necessary Norvir, Aptivus is cheaper, because the maker of ritonavir,
Abbott Laboratories, (in penance for their 400% Norvir price increase) has promised
to give away Norvir for free to anyone who needs 400mg or more per day; those who
only need 200mg have to pay.
Since the benefit of Aptivus likely depends on using it with Fuzeon, one
bright spot for salvage patients would be the roll-out of the proposed needle-free
Biojector system for administering the injectable drug. Initial reports are encouraging
and a study is underway to determine if administration site reactions are significantly
decreased.
Capravirine
The non-nucleoside reverse transcriptase inhibitor (NNRTI) capravirine is another
drug that followed a long and winding path, passing from Shinogi in Japan to Agouron
in La Jolla and finally to Pfizer. First used in patients in the late 1990s, clinical
trials were halted in 2001 when animal toxicity studies produced vasculitis in beagle
dogs. The drug languished for a year while researchers tried to sort out the problem.
Pfizer jump-started the development program in 2003, but at this point the drug had
already acquired the aroma of failure. As information dribbled in about rash, the need
for boosting, interactions with other drugs, and uncertainties about dose, capravirine
increasingly smelled like a goat. When long awaited phase II results finally came in
that showed no apparent efficacy benefit in treatment experienced patients, the handwriting
was on the wall. Still Pfizer soldiered on for another few months before finally ending
the not-so-wonderful life of capravirine in July 2005.
TMC114
This as yet unnamed protease inhibitor from Tibotec Pharmaceuticals, is chemically similar
to amprenavir, but has modifications that allow it to bind much more tightly into its active
site — even in HIV protease that has mutated to evade most conventional PIs. Like
tipranavir, TMC114 is active against HIV isolates resistant to other PIs and is very slow
to produce its own resistance mutations in the test tube. Unlike tipranavir, however,
TMC114, in its initial studies at least, is more tolerable and appears to generate far
fewer and less severe liver and blood lipid abnormalities than Aptivus. Although TMC114
still depends upon the curse of ritonavir boosting to get adequate amounts of medicine
into the blood (a dose of 600mg/100mg twice-a-day is going forward into phase III trials),
the drug is not expected to cause the dramatic kinds of drug-drug interactions that many
fear will make tipranavir so difficult to use.
In a phase II trial among patients with extensive prior PI exposure, TMC 114/ritonavir
at the 600mg/100mg dose produced an average viral load drop of -1.85 log and delivered 59%
of patients to below 400 copies at 24 weeks, although achieving these results was highly
dependent upon the inclusion of Fuzeon in the mix. This again underscores the importance
in the salvage setting of taking at least two drugs that are active against multi-drug
resistant virus. Rates of adverse events, primarily headache and GI upset, were similar
to those in the comparator group and serious increases in triglyceride blood levels were
observed in about 6% of subjects in all groups.
The FDA must have been impressed because in mid-June 2005 it gave the green light
for Tibotec to file for accelerated approval based upon its phase II trial results. This
surprise ruling allows TMC114 to leapfrog to the head of the new drug pipeline and the
announcement effectively stole thunder from the Aptivus debut a week later. If all goes
well Tibotec will likely submit its data in early 2006 and the drug could be in pharmacies
by summer. The company is planning to open an expanded access program in the fourth quarter
of 2005. If this drug pans out to be as effective and tolerable as it now appears, Boehringer
Ingelheim may wish it had sent tipranavir the way of capravirine as it watches Aptivus
sales sink beneath the waves less than a year after hitting the market.
One lesson from all of this is that the bar for acceptable toxicity and efficacy
is now set much higher, and drugs that looked promising in 1999 won't cut it in 2006
and beyond. Now, if we could only get rid of ritonavir boosting.
Aptivus® in the Hotseat
Excerpts from the FDA Hearings
By Bob Huff
These are condensed excerpts from discussions by the FDA Antiviral Advisory
Committee on the new drug application for Aptivus (tipranavir) 250mg capsules
indicated for treatment of patients with HIV.
May 19, 2005
During the first half of the daylong meeting, safety and efficacy data and
analysis concerning tipranavir/ritonavir (TPV/r, brand name Aptivus) were
presented, first by the sponsor, Boehringer Ingelheim (BI), and then by
the FDA. After making clarifying querys to the sponsor and FDA, the members
of the Committee discussed the formal questions posed to them by the FDA.
The Committee also voted on the key question of whether TPV/r was safe and
effective in the proposed population.
Janet Englund (Committee Chair): Welcome and turn off your Blackberries.
Englund: What is your risk/benefit assessment of TPV/r given the data
provided for safety and efficacy in the treatment of "heavily pretreated"
HIV-infected individuals?
Richard Haubrich: The evaluation of safety is in the context of need. The
biggest need in the clinic today is for patients with multidrug-resistant
HIV. This is who we clearly need new drugs for. The risk/benefit ratio is
different for these patients. The bar would be much higher for treatment-naïve
patients. We are willing to tolerate more toxicity and complexity in these
patients because we need new drugs. The promising drugs on the horizon won't
be available in the clinic on Monday morning.
Douglas Fish: Most of the safety issues with tipranavir are reversible. While
they are serious, they are manageable. But this is the reality of HIV care in 2005.
Maribel Rodriguez-Torres: I treat the complications. There is a need for a
treatment for patients with resistance. Why not approve tipranavir in combination
with Fuzeon? If not, then there should be a strong recommendation to use them together.
The prevalence of hepatitis C virus (HCV) is much higher in the clinic than
in these studies. It is as high as 60 percent in our Baltimore patients. Simply
measuring ALT does not tell enough about the severity of the disease. We need more
biopsies. Did patients with elevated liver function tests (LFTs) also have lipid
elevations?
I'm also concerned about so many drug interactions. How will garden-variety
treaters sort this out? I'm concerned about interactions with methadone —
we need to know about this. Remember, it is usually a different doctor who is
treating with methadone. How are we going to deal with women who may be treated
with hormones by another doctor? We need to give some paradigms that primary
treaters can follow.
Kenneth Sherman: I appreciate what Dr. Rodriguez-Torres said. From the
viewpoint of the hepatologist, it is the patients with end-stage liver disease
that are the problem. We see lots of patients dying of end-stage liver disease
with undetectable viral load. This study has short-term HIV endpoints. We have
seen nothing about prevention of opportunistic infections or long-term survival.
There was also a failure to address issues with early hepatic signals in
these trials. A high proportion of patients had high liver enzymes but
there was little attempt to get more biopsies to distinguish between those
with different stages of liver disease.
Short term use of these drugs does not occur. This is the last drug
for many people and it will be used for an extended period of time. The
concern is not short term flares, but patients who cruise along with
elevated LFTs for years. There is much more disease in coinfected
patients. BI recommends more monitoring in coinfected patients. There
is a poor understanding of liver injury in the community and there is
poor monitoring. But once you have symptoms, the game is over. You have
to worry about liver injury well before that point. While we are transplanting
more people with HIV these days, these patients with advanced HIV disease
are the least likely to be transplanted. Finally, drug-drug interactions
that may lead to increased liver toxicity have not been well characterized
to this point.
Lynda Dee: We have to look at the risks versus the benefits. Tipranavir
may have a limited role in the clinic. We're talking about heavily pretreated
patients. I think there has to be more education on what drugs can be taken
with this.
Robert Munk: I think we can characterize the patient population, but
what about the prescribing population? I don't think this can be turned
loose on the market without education. I'm concerned the package insert
won't cover all the issues. If I don't see a drug studied for interactions,
I presume it is benign. But there are many potentially serious interactions
with this drug that haven't been studied yet. I'm concerned about whether
tipranavir is ready for prime time.
Lauren Wood: The patients who need this will also likely have high baseline
LFTs. Clinicians will face situations with patients who need this drug who have
LFTs above the upper limit of normal. What do they do? The company should generate
data that tells us the magnitude of elevation over time. When you're talking about
grade 3 and 4 LFT elevations sustained over months and years, that has much different
implications for long term toxicity. We didn't discuss other parameters of liver
function such as coagulation studies.
Scott McCallister (Boehringer Ingelheim): Patients had AST or ALT elevations.
Coags were not elevated.
Victor DeGruttola: There appears to be a patient population that has a
favorable risk/benefit ratio for this drug. But how well can we predict who
will have liver toxicity and who will have virological response benefit? It
would be useful to put analyses together to classify how well you can predict
toxicity. Regression analysis doesn't do that.
Who will respond best? Doug Mayers made a crucial distinction between
mutations that have a direct causal impact and those that are merely associated
with mutations that have causal effect. If the mix of mutations does not change
over time, that's fine, but that mix could change and the L90 could cease being
associated with the causal mutations. What is the best classification for patients
who are likely to respond?
Englund: I'm anxious to get drugs that will benefit my patients and I
think I can follow and manage my patients. We should stress this drug's use
by experienced HIV treaters, but that is hard to do.
Gene Morse: One of the concerns I have is that these patients may
be on 8, 12, 15 drugs at a time. And many have coinfections. You can
identify who is most likely to be safe, but beyond that how will those
complex patients be managed? How will long-term toxicity be followed? We
need studies.
Robert Grant: We've seen data that established that a sub-group that
will benefit. I'd like to hear more about efficacy in the patients in the
boosted PI study. The proposed language of the indication mentions salvage
settings, but the people with the most resistance were excluded from the
data presented.
Douglas Mayers (Boehringer Ingelheim): A small percentage got
a durable drop, but most began to fail afterward. We've seen good
anecdotal information on the Fuzeon-naïve patient that combines
Fuzeon with tipranavir.
Englund: Let's go around the table and vote. Do the data demonstrate
that tipranavir/ritonavir (TPV/r) is safe and effective for the multi-drug
resistant HIV-1 infected population?
Wood: Yes
DeGruttola: Yes
Rodriguez-Torres: No. Drug interaction studies are needed, as well
as studies of histology and on the outcome of liver disease.
Munk: Yes
Sherman: No as a rapid approval pending long-term data and clinical outcomes.
John Gerber: Yes
Ronald Washburn: No. There is a need for long-term efficacy follow-up.
Grant: Yes
Veronica Miller — Yes
Frank Maldarelli: Yes
Morse: Yes
Edmund Capparelli: Yes
Stephen Hall: Yes
Englund: Yes
11 Yes; 3 No votes. All yes votes came with concerns and reservations.
Englund: Please discuss your highest degree concerns.
Hall: My concerns are with long-term outcomes and clinical management issues.
Capparelli: There needs to be a greater focus on use with other drugs. Few
thymidine NRTIs were used and there was little variety in the background regimens.
Morse: My problem is that I can't tell my patient how well this will work.
Maldarelli: Efficacy is evident because new resistance mutations emerge, but
the durability of the viral response remains uncertain.
Miller: I am concerned with long-term liver toxicity. It is too bad
that 48-week data was not available. We need more information on rash, including
its clinical management and the role of CD4 count in predicting rash. We should
stress the need for physician expertise in using this drug.
Grant: I agree we should emphasize that the use of this drug in these patients
should be restricted to experts. I'm concerned that the evidence is not yet sufficient
to justify the risk/benefit ratio in women, particularly women on birth control pills.
Washburn: I remain unconvinced that the risk/benefit ratio is acceptable
based on a summary of data from a short-term, unblinded trial.
Gerber: A drug proposed in this advanced population — especially a drug
with these interactions — should have some clinical endpoint. We also need
to see information on interactions with fibrates and lipid lowering drugs.
Sherman: If pretreatment status shows elevated LFTs, then patients should be
thoroughly evaluated for stage of liver damage.
Munk: More drug-drug interaction studies are needed as are more studies of
treatment in co-infected patients and in women. Better characterization of
resistance is also needed.
Rodriguez-Torres: I agree with Dr. Sherman to fully workup patients for liver disease.
DeGruttola: It is very hard to interpret the surrogate endpoints here — we
need clinical endpoints. It is also important to make the best use of mutations at the
start of treatment. A person with a 1.0 log drop, but still not undetectable, was counted
as a success in this study. We need to know more about durability. We need to know how
to classify those patients who are at most risk and those at low risk of toxicity.
Wood: It is also important to tell clinicians that there is no indication for
this drug if a patient has susceptibility to other protease inhibitors and that
this would be the only PI allowed in a regimen. Make that clear. It also needs to
be reinforced that tipranavir needs to be accompanied by another active drug to gain
the maximum benefit. Another priority focus for interaction studies are diabetes
drugs. Also, look at additional oral contraceptives in women. That has to be at
the front gate.
Dee: What authority does the agency have to recommend education to doctors?
Debra Birnkrant (FDA): We think there should be adequate educational materials. We
never seem to learn whether these educational program work or not. We never get a testing
of the materials in a large group. But we don't regulate this.
Fish: The short follow-up of 24 weeks is a casualty of accelerated approval.
Princy Kumar: I have a different take on this compared to my hepatologist
colleagues. As a clinician looking at who was treated in these trials, I see an
extremely treatment-experienced group of patients. Of course we worry about safety
in these patients. But all the concerns should not deter from the fact that at the
present time this is one of the few agents we have that can work in this group. As
Dr. DeGruttola asked, which patients can we give this to safely? No single agent
is going to be durable if it is the only active agent. What can be done to allow
other, more potent drugs down the line to be added to this drug?
Haubrich: My comments are closely aligned with Dr. Kumar's. There is no way
this study could show clinical benefit since it was designed to let people drop
out if they were failing. Doing a study like that would be infeasible because you
would have to keep people on a control arm. I hope people will stay away from that
idea.
Janet Englund: My summary: We as a committee feel that the need for this drug
is high, but the risks are present. We want to know about long-term durability. We
need to know clinical incidence rates over the long term. We have questions as a group
concerning management of toxicities; drug-drug interactions; about the lack of women
in the trials. To hear that the ongoing studies are not preferentially set up to enroll
women is troubling. We need much more information on hepatic function follow-up and
on the prediction of toxicity and rash incidence.
The full transcripts can be found at
www.fda.gov.
Aptivus for the Rest of Us?
Janet Englund: The limited amount of data on females with
HIV infection in the TPV program shows an increased incidence of rash in females.
Please provide your recommendations for investigation of this safety signal in
future studies with TPV.
Veronica Miller: I'd suggest that older women not on birth
control also be studied, i.e., women on hormone replacement therapy.
Lauren Wood: It should be recommend in the label how to manage
individuals with rash. It is encouraging that there is no evidence of Stevens Johnson
Syndrome. But do you treat through if there is rash? Or discontinue and rechallenge?
It would be a disservice to deny access of the drug to women.
Janet Englund: After so many years on this panel, I'm getting
ready to recommend that a drug not be licensed if there is so little data on women.
|
HIV Vaccine and Pathogenesis Update
The 2005 HIV Keystone Symposium
By Gareth Hardy, PhD.
The 2005 HIV vaccines and pathogenesis Keystone Symposia, took place
in Banff, Canada in early April 2005. This latest unveiling of cutting
edge research in HIV vaccine developments and pathogenesis was set high
in the alpine landscape of the Alberta Rocky mountains at the grand Banff
Fairmont Springs hotel, a location that brought images of Jack Nicholson
to mind.
I anticipated this latest convergence of the great and the good of
HIV immunology as yet another update on what we still can't figure out.
But instead — and I may be misjudging things — I couldn't help
feeling that incremental progress is underway that may lead to substantial
developments in the next few years. This isn't because of any new clinical
data on vaccines in development or suggestions of protection in vaccinated
cohorts or animal models, unfortunately. But more because it seems to me
that we could finally be starting to get a handle on some significant obstacles
to our understanding of HIV pathogenesis and mechanisms of immunological
protection.
All currently effective vaccines that protect against viral infections
do so through elicitation of neutralising antibodies (antibodies that block
the function of their cognate antigen) — and there is now a general
consensus that a vaccine capable of preventing HIV infection (a prophylactic
vaccine) must also induce effective neutralising antibodies. Cell mediated
responses, involving T cells, play a much greater role in the control of
infection once it is established and in sterilising immunity, in which an
established infection is cleared. But in order to be effective in the long-term,
neutralising antibodies must be able to overcome the diverse variety of
mechanisms that HIV utilizes to evade antibody responses to its envelope
protein. These mechanisms include the shielding of potential epitopes by
sugary glycan molecules, conformational masking, hypervariabity in immunodominant
loops, and occlusion of conserved regions of both gp120 and gp41. To be
effective, neutralising antibodies must be both broadly cross neutralising
(inhibitory to a wide diversity of different viral strains) and they must
be present in sufficient quantities at the mucosal surfaces where they will
encounter HIV as it enters the body, and block infection. If a vaccine
candidate can actually meet these requirements, it is quite likely it will
be successful in protecting against HIV infection. The role of such vaccine-induced
neutralising antibody responses in those already infected is speculative,
although it is possible that protective responses may also have a therapeutic
application.
Pushing the Envelope, Even Further
Alexandra Trkola of the University Hospital Zurich, Switzerland,
gave an update on data presented at last year's symposium with some additional
material in which 8 chronically infected and 6 acutely infected patients stopping
antiretroviral treatment (ART) were treated with a cocktail of three such broadly
cross neutralising monoclonal antibodies: 2G12; 2F5; and 4E10 (1). These patients
were selected for the study according to the sensitivity of their viral isolates
to the three monoclonals. ART was administered for at least 3 months. Starting
one day before stopping treatment, patients received 13 passive immunizations
over 11 weeks, with two in the first week. Follow up lasted for a total 24
weeks. Two of 8 chronically infected patients controlled their viral load
during the 11 week passive immunotherapy period and one controlled virus for
the whole 24 week period. In contrast, far better control was seen in those
patients with acute HIV infection. All 6 of these patients controlled their
viral load for at least 5 weeks of the passive immunotherapy period and 2
patients controlled viral loads beyond 12 weeks. Viral rebound in the acutely
infected patients was compared to that in a control group of 12 acutely infected
patients discontinuing ART. The difference in time to viral rebound between
the monoclonal antibody treated and the nontreated acutely infected patients
was statistically significant (P = 0.0286).
During treatment, sequential viral isolates were obtained and assessed for
sensitivity to the three monoclonal antibodies. While no relevant changes were
seen in sensitivity to 2F5 or 4E10, or any sequence changes in the epitopes
they recognise, there was substantial resistance of rebounding virus to 2G12
in 11 of 13 patients that originally had 2G12 sensitive virus. It was noted
that the ratios of 2G12 antibody concentration in the plasma to in-vitro
inhibitory doses were significantly higher in patients who responded than
in patients who did not (P = 0.0175). It thus seems that variations in activity
of 2G12 between individuals and therefore the dosing of 2G12 are a likely
influence on the outcome of this study. Nevertheless, seven of 14 patients
responded to passive immunization with a cocktail of 3 broadly cross neutralising
antibodies with clearly defined delays or decreases in rebounding viremia. This
provides the first direct evidence that these neutralising antibodies can contain
viremia in HIV-infected patients. If such antibodies could be elicited by an
immunised host, then the likelihood of containing viremia in the long term would
be far greater, since production of antibodies by B cells recognizing sensitive
epitopes (originating from a vaccine) would have broader specificity than just
the three epitopes recognized by these monoclonals.
Richard Wyatt of the Vaccines Research Centre, National
Institute of Allergy and Infectious Disease, National Institutes of Health,
Bethesda, MD, USA, further added to our understanding of these antibodies
with some rather surprising discoveries (2). The antibodies 2F5 and 4E10 bind
to a region on gp41 called the membrane proximal region (MPR) which is highly
conserved. Until recently immunologists had considered that this space, located
in the juncture between gp120 and the viral membrane, was too small for an
antibody to gain access to any relevant, conserved epitopes. The number of
angstroms between the underside of gp120 and the hydrophobic plasma membrane
of the virus was just too few for a large antibody molecule to fit in, thus
occluding the membrane proximal region.
Wyatt et al deployed atomic-level structural information coupled with
biochemical, biophysical, antigenic and immunogenic analysis to create novel
protein immunogens capable of generating antibodies with broadly cross neutralising
activity against HIV. His experiments demonstrated that, far from the two neutralising
antibodies being occluded from the membrane proximal region of gp41 by the lipid plasma
membrane of the virion, they are actually dependant on the close proximity of the
plasma membrane for their interaction with the region. These findings were somewhat
remarkable because it was not previously thought that antibodies would interact with
the plasma membrane, and rather would be repelled by it. I guess this was one of my
reasons for coming away from this meeting with a feeling of optimism, because at least
from this presentation it is clear that the immune system is far cleverer at dealing
with a highly complex problem than we sometimes give it credit for.
Adding more optimism, I caught up with my colleague, Jason Hammonds,
of Vanderbilt University, Nashville, Tennessee, and followed him on a mile-high trek
to the summit of Sulphur Mountain, in which our path was crossed only by a family
of elk. Hammonds has previously described the construction of pseudovirions which
express stable gp120 trimers altered to the CD4 bound conformation (3), which is
known to reveal a greater extent of the highly conserved membrane proximal region
of gp41. At this meeting Hammonds presented his most recent data (4) comparing the
env expressing pseudovirion against a soluble gp120 preparation in Guinea pigs. In
the pseudovirion immunized animals the neutralising antibody responses displayed were
of a significantly greater breadth and magnitude than those from the soluble gp120
immunized animals. High titres of neutralising antibodies were found that neutralised
every strain of virus Hammonds tested including not only lab-adapted strains of virus,
which are relatively easy to neutralise, but also primary isolates, suggesting that
the CD4i gp120 trimer-expressing pseudovirions do indeed induce production of broadly
cross-neutralising antibodies. Although these animals are not a model for HIV, the
fact that the pseudovirion immunogen is inducing these hard-to-generate antibodies
is very encouraging. Primate and/or human studies are eagerly anticipated.
Dendritic cells: A Trojan Horse from Mucosa to Lymph Nodes
Turning to events that take place at the initial stage of infection, which may
be blocked by novel agents, Andrew Blauvelt of Oregon Health and Science University,
Portland, Oregon, discussed the role of an epithelial population of dendritic cells
called langerhans cells (5). The role of langerhans cells in establishment of
infection has remained somewhat controversial for a number of reasons. Namely,
these dendritic cells (DCs) are relatively uncommon in the mucosal epithelium,
where they constitute only about 1–2% of the cells present; their expression of
HIV co-receptors changes rapidly (within hours) from CCR5+/CXCR4- to CCR5-/CXCR4+
upon maturation of the cell; and these cells migrate rapidly (within hours) from
epithelial tissue to draining lymph nodes upon exposure to HIV. Blauvelt and
workers developed a skin explant model to investigate the interaction of HIV
with immature langerhans cells in the epithelium (6) and showed that langerhans
cells are the initial targets of HIV following virus exposure.
In order to obtain langerhans cells from mucosa, Blauvelt carried out
blister inductions in healthy volunteers. Langerhans cells were derived from
blister roofs in a 4 day culture experiment. Histological analysis demonstrated
that the squamous epithelial cell content of this tissue was very similar to that
of the vaginal mucosa and internal and external foreskin. These immature langerhans
cells were co-cultivated with different strains of virus including CCR5 tropic
(R5) virus (BaL) and CXCR4 tropic (X4) virus (IIIB) for a 2 hour period in which
infection readily took place. Among other things, Blauvelt showed that:
w immature langerhans dendritic cells become productively infected with R5
virus by a CD4 and CCR5 dependent process;
- R5 virus infects immature langerhans cells more efficiently than X4 virus;
- infection of immature langerhans cells by R5 virus is regulated by CCR5 polymorphisms; and
- infection of immature langerhans cells by different CCR5 polymorphisms of R5 virus
can be blocked by an analogue of CCR5's ligand, RANTES, called PSC-RANTES;
Blauvelt showed that infection of immature langerhans cells could be
prevented by incubation with PSC-RANTES, before and during the 2 hour co-culture
with virus. He also explained that immature langerhans cells from those individuals
who were heterozygous for the delta32 mutation in CCR5 had a much higher degree
of protection from HIV infection by PSC-RANTES than those cells from individuals
with homozygous wildtype CCR5.
One aspect of this and other similar work presented at Keystone which
concerned me, was the lack of validation of these inhibitors in rectal muscosa
models. Is the rectal mucosa much different from the vaginal mucosa? Or are
there key differences in rectal and vaginal transmission? I couldn't help wondering
that if microbicidal gels containing agents such as PSC-RANTES are going to be
effective, then they will have to be available as over-the-counter products.
But if we don't know that such agents are equally protective against rectal
transmission, as against heterosexual vaginal transmission, then a switch in
"safer sex" practices from condoms to gel could, paradoxically, have the
counter-productive effect of increased rates of infection in gay men who
have anal sex — and for that matter, in heterosexuals who have anal
sex. But I guess, for some reason, I just wasn't brave enough to stand up
in front of all those suits and ties and say "Hey look, some of my best
friends are straight, and they tell me that straights have anal sex too!"
Ashley T Hasse, of the University of Minnesota, Minneapolis, Minnesota,
described the small window of opportunity for establishment of infection
that exists at the very earliest stage of exposure to HIV but how the
immune response fails to close that window because it is too little and
too late (7). Hasse explained that despite the large innoculum of virus
present during sexual transmission, most of that virus is cleared at
the mucosa. Thus initially only a very small founder population of virus
gets through, which has to extensively amplify itself in order to establish
infection.
Using the SIV model in rhesus macaques, the initial events of acute
immunodeficiency virus infection were tracked following intra-vaginal
infection. At 4 days from infection the tissue distribution of SIV RNA
within the endocervix was extremely focal and extremely small. By da y 7
there was a 70-fold expansion of SIV RNA with substantial disseminiation.
At day 6 the first infected cell appeared in the mesenteric lymph nodes.
Hasse explained that the virus thus follows an anatomical spread as such:
Mucosa → Draining lymph node → Spleen/Gut
During this process, explosive SIV replication takes place in the
mucosa as virus encounters resting memory (CD45RO+) CD4 T cells as well
macrophages and dendritic cells (DCs). Resting memory CD4 T cells express
intermediate levels of CCR5 and act as a portal for virus dissemination
to the lymph nodes, where activated CD4 T cells then support a massive
explosion in virus replication. Thus it is described that both memory CD4
T cells and DCs have roles to play in viral dissemination. Following this,
a huge loss of memory CD4 T cells takes place in the gut-associated lymphoid
tissues (GALT). Here large numbers of memory CD4 T cells were found to be
expressing caspase-3, an apoptosis (regulated cell death) marker, along
with cell surface markers for apoptosis susceptibility including FAS (CD95)
and FAS ligand (CD95L), suggesting that memory CD4 T cell loss in the GALT
is mediated by both direct and indirect viral mechanisms. The subsequent
CD8 T cell response is too late and too small to protect against this
damage, although a robust response was observed in the female reproductive
organs. This was associated with a reduction to very few residual SIV
infected cells in the genital tract by 28 days following infection.
In alternate primate hosts, the consequences of DC entrance dictate... life and death.
Mark Feinberg, of Emory University School of Medicine and Emory Vaccine
Center, Atlanta, Georgia, showed some very nice work in primates highlighting
important distinctions between diverse clinical outcomes in different species
(8). Sooty mangabeys are the natural hosts for SIV infection. Despite high
levels of plasma viremia in these animals, there is no CD4 T cell depletion,
no elevation of CD4 or CD8 apoptosis, no increased CD8 T cell proliferation
and no disease progression. Interestingly, depletion of CD8 T cells in these
animals had no effect on viral load, suggesting that the limited SIV-specific
CD8 T cell responses in these animals had no effect on viral activity. Also,
these animals are fully able to respond to and control other viral infections.
Therefore it appears that in sooty mangabeys, a relative state of clonal
non-responsiveness exists, and that despite high viral turn-over (sometimes
greater than in HIV infection in humans and pathogenic SIV infection in other
primates, e.g. rhesus macaques) the lack of immune activation in these animals
is the principal condition which correlates with disease protection. To better
understand the cellular and molecular basis of whether or not chronic immune
activation and immunopathology follow immunodeficiency virus infection, Feinberg
and colleagues studied divergences in the innate and adaptive immune responses
to SIV in sooty mangabeys and rhesus macaques respectively. Differences in DC
activation and migration in response to SIV were apparent within the first days
of infection, which were subsequently followed by substantive differences in
the magnitude and type of adaptive immune response. These differences in in-vivo
responses were mirrored following ex-vivo exposure of sooty mangabey, rhesus
macaque and human plasmacytoid dendritic cells (pDCs) to specific Toll like
receptor (TLR) ligands and to inactivated virus. pDCs of sooty mangabeys failed
to mature or express CCR7, which would home them for the lymph nodes upon exposure,
in contrast to the pDCs of humans and rhesus macaques. In addition there was also
a significant diminution in production of IFN-a. Feinberg explained that this was
apparently the result of divergent propagation of activation signals along post
receptor pathways. While both sooty mangabeys and rhesus macaques were able to
produce IFN-a2 in response to influenza virus, only rhesus macaques produced
IFN-a2 in response to inactivated SIV. At the organism level, gene expression
profiling studies further indicated that a major feature which distinguishes
pathogenic from non-pathogenic immunodeficiency virus infection is the extent
to which a pattern of type-1 interferon production and response profiles
manifest. Interestingly, Feinberg pointed out that Type-1 interferon genes
were amongst the most strongly up-regulated in T cells of HIV infected
humans, in stark contrast to SIV infected sooty mangabeys. Feinberg
concluded that a genetically programmed generative stage failure of sooty
mangabey innate immunity to respond to SIV infection, manifesting as lack
of pDC maturation and migration to the draining lymph nodes, represents
the first divergence in host immunity between species, which determines
differing infection outcomes between these species.
T cell responses in chronic HIV infection: A different set of problems,
with a different set of solutions?
Following my concern on the subject after last year's Keystone meeting, I
was very pleased to see the duel cytokine interleukin-2, interferon-gamma
(IL-2/IFN-g) story getting more mileage this year, as a replacement for
IFN-g single parameter measurements. Building on the work of Marc Boaz
in London, who originally described this duel phenotype in long-term non-progressors,
Souheil-Antoine Younes in Montreal and Alexandre Harari in Lausanne have confirmed
that this phenotype of antigen-specific T cells is a useful correlate of immunity,
at least in infected individuals. Complex multi-colour technology is gradually
unravelling a not very clear picture of T cell differentiation, in mice and
men differentially, using markers such as CCR7, CD45RA, CD62L, CD27 and CD28. In
addition CD127, the IL-7 receptor a chain, has also entered the fray as a likely
contender for the distinction of small numbers of short-lived effector memory T
cells which have a tendency to survive into the long-lived central memory T
cell pool, although the directional differentiation between these subsets is
debated. Such T cells are now being considered critical components of protective
T cell responses, which are thus likely to become correlates of immunity in
cohorts of "protected" patients. However, leaving aside the high-tech revolution
in multi-colour flow cytometry, an alternate handle on the same, or similar,
effector memory T cell responses, liable to generate long-lived central memory,
is the duel IFN-g/IL-2 expression phenotype. In larger scale vaccine trials an
assay, be-it ELISpot or flow based, for this duel cytokine phenotype may represent
a high through-put alternative to complex multicolour flow technology, which is
not available in many parts of the world.
Steven Deeks of the University of California, San Francisco, CA, USA,
described T cell responses in a cohort of patients who maintain low-level
viremia in the presence of high-level drug resistance, ("partial controllers
on antiretroviral therapy", PCAT) (9). In these patients, Deeks and co-workers
observed that:
- HIV is often constrained in its ability to develop high-level drug
resistance while maintaining replicative capacity;
- immune activation is reduced in patients with drug-resistant virus, in comparison
with patients with similar viral loads composed of wild type virus and;
- HIV-specific T cell responses are often very high during incomplete viral
suppression.
Deeks explained that the immunologic characteristics of this group
of patients were very similar to those of long-term non-progressors. Low
levels of activation and spontaneous proliferation were one such parallel.
Surface expression of the activation markers CD38 and HLA-DR on CD4 T cells
of patients with multiple drug resistant virus were significantly lower than
those of patients with wild type virus and similar viral loads. Another such
shared characteristic between long-term non-progressors and PCATs were well
preserved HIV-specific IL-2 and IFN-g-high producing CD4 T cells. Deeks showed
that the percentage of CD4 T cells which responded to HIV gag with a duel
IFN-g/IL-2 phenotype in long-term non-progressors (n=17) was significantly
greater at about 0.4–0.5% of lymphocytes, than in patients receiving HAART
whose virus was fully suppressed (n=40) at about 0.05–0.1% of lymphocytes,
P=0.01. When looking at patients with multiple drug resistant virus, who
partially control virus, the percentages of IFN-g/IL-2 co-expressing gag-specific
CD4 T cells were equivocal with long-term non-progressors. Deeks concluded
that control of viremia in PCATs is associated with an IFN-g/IL-2 CD4 T cell
response as seen in long-term non-progressors, and that both groups of patients
are able to maintain this population without exhausting the CD4 response.
Turning to CD8 T cell responses, Michael R Betts of the Vaccine Research
Centre, National Institute of Allergy and Infectious Diseases, National Institute
of Health, Bethesda, MD, USA, presented his work on polyfunctional T cell phenotypes
in long-term non-progressors and progressors (10). This work was expanded on by Richard
Koup, head of that lab, in one of the plenary sessions. An abundance of evidence now
clearly implicates CD8 T cell responses in protection from disease progression and
control of viral replication in HIV-infected individuals. Although these responses
are thought to play a role in long-term non-progression, Betts points out that the
magnitude of CD8 T cell responses between progressors and non-progressors is not
notably different and few comparative differences in CD8 T cell responses between
the two groups have been identified. Betts explained that using 11 parameter flow
cytometry his group analysed the CD8 T cell responses of 9 long-term non-progressors
and 79 progressors. They identified a five-function panel in CD8 T cells consisting
of the inflammatory cytokines IFN-g, IL-2, TNF-a, the chemokine MIP1-b and the
degranulation marker previously described by Betts, CD107a. Using FlowJo software,
31 potential populations were possible with these 5 parameters. They found that
long-term non-progressors maintained a polyfunctional CD8 T cell response with 4
or more of these 5 markers in response to HIV proteins: gag; pol; env and; tat/rev/
vif/vpr/vpu. This response tended to include IFN-g, TNF-a, MIP-1b and CD107a with
or without IL-2. In response to HIV antigens, the 5 function phenotype consisted
of approximately 10% of the CD8 T cell response. This response was markedly deficient
in progressors and there was no improvement after the first few months of HAART. I
asked Betts if they planned to assess these responses in patients who had been on
longer term stable HAART and he agreed that this was an important aspect of their
follow up. Interestingly Betts and his team also found that this response was a
normal component of the CD8 T cell responses against CMV, EBV and flu in progressors,
long-term non-progressors and uninfected individuals.
Rick Koup expanded on this work describing that the 5 functional
(IFN-g/ IL-2/TNF-a/MIP-1b/CD107a) population had a trend towards, but was
not exclusively, a central memory phenotype (CD45RO+/
CD27+/CD57-). While IL-2 expression tended to be the main difference between
5 and 4 function CD8 T cell responses, as the number of functions dropped to
3 functions the cell surface phenotype tended to become more of an effector
type (CD45RO+/CD27-/CD57+/-). Koup described some investigations of CD4 T
cell responses with these parameters, and explained that the proportion of
IFN-g/IL-2 expressing CD4 T cells was significantly higher in long-term
non-progressors than progressors. In cohorts of DNA and adenoviral HIV
vaccinated patients, a major component of the polyfunctional CD4 T cell
response tended to comprise IFN-g and IL-2, without TNF-a. This was in
contrast to other cohorts of CMV infected or vaccinia virus immunised
subjects who elicited a mainly IFN-g+/IL-2+/TNF-a+ response. Thus, in
conclusion, although similar quantities of HIV-specific CD8 T cells may
be apparent in both long-term non-progressors and progressors, long-term
non-progressors have a qualitatively superior CD8 T cell response to
HIV. Consideration of multiple parameters of functionality are important
in the determination of protective responses, both with regard to CD4
and CD8 T cell responses. While this data confirms that IL-2, together
with IFN-g, is an important co-feature of protective CD4 T cell responses,
it is evident that MIP-1b is likely to be at least as equally an important
feature of polyfunctional CD8 T cell responses.
The implication of this is that single parameter measurements of T
cell function in vaccine and immunotherapy trials are becoming outmoded,
partly by technological developments, but more so by a realization that
what constitutes a protective T cell response is likely to involve multiple
simultaneous functional parameters, that must be co-incident. For the purposes
of simply defining the numbers of antigen-reactive T cells in immunogenicity
studies, single parameter IFN-g assessment is a good choice as an endpoint.
But for vaccine trials and studies which seek to identify correlates of
protective immunity, and to determine the nature of responses we must induce
in infected patients and alternately in unexposed populations in whom we wish
to confer protection from infection, the board is thrown open to a diversity
of players. Such studies will need to include measurements of polyfunctionality
in CD4 and CD8 T cell responses, in order to determine which are the protective
phenotypes. We are starting to get a real handle not only on what kind of responses
to look out for, but possibly also on how to go about manipulating the generation
of those responses we should be looking for. On many fronts, I sensed hope on
the horizon. I flew home, still somewhat jet-lagged, and a little weary from
the altitude and dry air, having only had time for one afternoon's skiing, but
content in the knowledge that some exciting progress is being made, and that
somewhere, amongst the firs, a young family of elk are seeing the winter snows
give way to the coming of summer.
Gareth Hardy is a senior non-clinical research fellow based
at the Department of Immunology and Molecular Pathology, Royal Free & University
College Medical School, London, United Kingdom, specialising in immune responses
and reconstitution in HIV infection with a special interest in T cell function
and immunotherapy.
Playing God in Kathmandu
By Rajiv Kafle
A Danish musician from the sixties wrote a song about Kathmandu: "The
streets are made of rubber — take off your shoes and walk on them."
In a present day Kathmandu if you take off your shoes there is a chance
that you will get pricked by a needle. Over 70% of drug users living in
this historic city are infected with HIV. However this neither rings an
alarm for the government nor for the development partners working in Nepal.
Our government is silent because it is in denial. The development partners
are silent because Kathmandu is neither strategically nor politically important
for them. For example, the Global Fund has overtly ignored the challenges it
is facing in this country. Some time back a former board member of the Fund
wrote to me: "Unfortunately Nepal is not a priority for the Fund."
Tourists traveling to Nepal in the early sixties wondered if Kathmandu
had more temples than houses where people lived. If so, then it obviously had
more gods and goddesses than people. Maybe it was true for the sixties but not
anymore. As far as gods and goddesses, though, in the past few years I have
turned into one myself. And it is really a difficult job.
So what are my responsibilities as a god? One of my major roles is to
decide who lives and who dies. In the Hindu religion we believe in reincarnation,
so it is easier for me to decide who should die now and be reborn and who should
live this birth itself. This year I have already permitted a few people to
die. Can you believe it?
Recently a guy came to me and asked me for help. He had TB and was living
with HIV for the past several years. He was poor and had no one to look after
him. He was weak and weary. I decided to help him out since I had some funds
for his basic checkups, for some ARV drugs, if he needed them, and TB treatment
was available for free. I welcomed him to my care home. He was immediately
put on anti-TB treatment and his CD4 was checked. He needed ARVs too. His CD4
count was less than 50.
Now the challenges begin. We only had a nevirapine combination (AZT, 3TC & NVP)
available to us. We had to find money to put him on an efavirenz combination
since he was also on TB medication. Then he showed signs of anemia and we
changed his regimen again. Then he started complaining about losing his eye
sight. The doctors suggested that it could be CMV or it could be toxoplasmosis,
etc. And then it was time for me to decide if he is to live or be left to
die. And he is not the only person I am looking after.
I cannot afford to keep him alive.
This is not the world we wanted for people living with HIV. This is not
what activists around the globe are fighting for. AIDS has divided this world
into two. One for the rich where clinical trials are underway for a new generation
of improved ARV drugs, and one for the poor where people still have to live at
the mercy of Gods like myself.
Rajiv Kafle is the coordinator of Navairan Plus, in Kathmandu, Nepal.
The Invisible IDU
By Daniel Raymond
Do we still have an HIV epidemic among injection drug users in the United
States?
The Centers for Disease Control (CDC) made headlines in June by presenting
new estimates that over a million people in the U.S. are HIV-positive. Coverage
of the National HIV Prevention Conference focused heavily on two overlapping
groups — men who have sex with men, and African-American men and women— who collectively
account for the majority of new infections. Injection drug use was virtually absent
in media accounts, reflecting a broader marginalization of IDUs in current HIV
prevention discussions.
It would be natural to infer that the omission of IDUs reflects a shift in
epidemiology — if we're not talking about injection drug use and HIV anymore,
presumably it's no longer a problem. One might imagine that the HIV epidemic among
IDUs has peaked or has been contained through needle exchange and harm reduction
measures. Indeed, by some measures this is true: the percentage of new AIDS diagnoses
attributed to HIV infection through injection drug use has been declining for several
years. And needle exchange is credited with dramatically slowing the spread of HIV.
In New York City, for example, HIV prevalence among IDUs fell from 55–60% in the
early 1990s to about 15% today.
Yet these numbers belie the fact that injection drug use directly accounts
for about one in four of all HIV infections and indirectly contributes to even
more infections through sexual transmission. Among women, the majority of HIV
cases result from injection drug use or sex with an HIV-positive IDU — yet
drug injection rarely figures into discussions of women and HIV.
Moreover, the success of needle exchange in New York City and elsewhere has never
been fully realized. Local political opposition has blocked needle exchange across
the country. Even established programs struggle to survive — the San Francisco Needle
Exchange, focused on young injectors, almost lost their city funding this year, while
Puerto Rico's health department is shifting needle exchange funding away from existing
programs and towards inexperienced agencies. The most recent national survey of syringe
exchange programs (SEPs) found that "in 2002, for the first time in eight years, the
number of SEPs, the number of localities with SEPs, and public funding for SEPs decreased
nationwide."
A new study on the cost effectiveness of various HIV prevention strategies
gives new urgency to local struggles for needle exchange and syringe access. Researchers
from the RAND Corporation and Tulane University calculated that needle exchange programs
in high- and medium-prevalence cities could prevent nearly 2,700 HIV infections each
year. The report concluded that interventions prioritized by the CDC's Advancing HIV
Prevention (AHP) initiative would fail to meet targets for reducing transmission. The
CDC's HIV Prevention Strategic Plan aims to reduce HIV infections to 20,000 per year
by the end of 2005 — an impossible goal to reach, given current infection rates.
< p>The CDC has effectively reshaped the discourse — and redistributed the
funding — on HIV prevention over the last few years. AHP's four main interventions
(making HIV testing part of routine medical care; expanding rapid testing in community
settings; focusing prevention efforts on people living with HIV ["Prevention with Positives"]
rather than those at risk; and further reducing mother-to-child transmission) pay scant
attention to the prevention needs of IDUs. Direct funding for community-based prevention
for people at risk requires adoption of one of a short list of "evidence-based interventions,"
only two of which directly address HIV risk through drug injection.
If it sounds like the CDC has written off HIV prevention for IDUs, part of the
problem is the on-going exodus from the agency of leading researchers like Richard
Garfein and Steven Jones, leaving a dearth of expertise and loss of focus on drug
injectors. But much responsibility lies with the ban on federal funding of needle
exchange written into federal appropriations bills by Congress. The federal ban has
effectively starved syringe exchange programs of adequate funding and limited their
growth and impact. Needle exchange and harm reduction remain controversial within
Congress and the Bush Administration. Rep. Mark Souder held a hearing in February
designed to discredit harm reduction, while U.S. representatives made an unsuccessful
attempt to pressure UNAIDS' Programme Coordinating Board to expunge references to
needle exchange from a new HIV prevention strategy document.
IDUs and needle exchange advocates are in desperate need of political
leadership and will at both local and federal levels. The CDC may claim its
hands are tied by the federal funding ban, but it compounds the problem by
rendering IDUs invisible in HIV prevention.
© 2005 Gay Men's Health Crisis
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