Chelsea & Westminster Hospital.
Medical Consultant
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PAEDIATRIC SALVAGE THERAPY
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Interview by Polly Clayden, ATP.
Multi-drug regimens for kids may be even more important than for adults - especially when they have developed resistance to existing drugs. Some of the most innovative, caring and impressive approaches to paediatric care have been developed by Dr Grace Aldrovandi MD. Dr Aldrovandi is an Associate Scientist at the Center for AIDS, University of Alabama at Birmingham, AL, USA. She is Protocol Chair of the PACTG1007 (Multi-Drug Antiretroviral Therapy for Heavily Pre-Treated Pediatric AIDS Patients: A Phase 1 Proof of Concept Trial).
Grace Aldrovandi was described to me as 'a brilliant scientist, compassionate clinician and treats HIV as if it were something that could kill a child (imagine that!)'. She works at the University of Alabama and is currently running a trial using mega-HAART in very drug-experienced children. This term for intensive multi-drug therapy was first associated with Julio Montaner who's strategies for heavily pre-treated adults, she admires, and she enthuses 'When I heard about what he was doing in Canada, I just wanted to go there and pay homage, at last it's got a name, it's respectable'.
Her protocol is called PACTG 1007 which amuses her because, 'It's been a great gift to my critics, 007 - you know what that means? Licence to kill! 'I want to kill this virus! As a virologist I know that strictly speaking you cannot kill viruses as they are not living organisms but emotionally that is what I want to do'. She has tremendous optimism, and uses a word usually approached with caution in HIV (or replaced with David Ho's rather measured 'eradication') - 'I use a lot of four letter words in my lab, and one of them's cure, I think you have to have high hopes and go for gold'. It was most refreshing to interview a doctor, not only brilliant and compassionate, but also not afraid to use the C-word!
Before setting up this trial how long had you been treating kids with multi-drug therapy, in this way, off-study?
"I would say we first began over three years ago. Kids were coming to us really heavily pre-treated and resistant to everything with viral loads in the millions and CD4s of nothing."
So well before mega-HAART gained currency as a term, were you trouble-shooting?
"Yeah, it was pretty similar to what they were doing with adults - Montaner, you know how he got started? It was the patients who drove him to it."
In your protocol you make heavily pre-treated children analogous to multiple-relapsed cancer patients and therefore use very intensive therapy, was this considered a very radical approach?
"Everybody thought I was joking but I thought about it and it just kind of made sense, I've always been intrigued with how people cured leukaemia in the early days. So I picked up a lot of standard oncology textbooks, as you saw in the protocol and tried to learn. I was fascinated by the relationship between DOSE intensity. If you use too few drugs and/or a lower dose of chemo, the remission rate does not change but the cure rate does. For example, in childhood, all (acute lymphocytic leukaemia) children who received 94% or less of their chemo were 5.5 times more likely to relapse than those who received 99% of the chemo. However, remission rates, (initial response) was identical. Similar effects of dose intensification have been seen with breast, colon, ovarian and many other types of cancer. When lower doses, or fewer drugs, have been used to avoid toxicity rates, cure rates have decreased."
"The way I think of it now is when we get people undetectable, we have got them into a sort of remission - some people object to the analogy and they're saying that people in cancer remission don't have latent cancer but clearly they do. And although we don't understand what governs relapse in cancer we understand more about it (or think we do) than with HIV."
So using the cancer model, given the kids' poor prognosis and that this treatment is probably their last and best chance - it makes sense to nuke it?
"Exactly. Considering how difficult this experienced population is to get suppressed, particularly with kids who are harder to treat anyway - they have higher viral loads. Not all the data, but a lot of the data points that virologic response is related to your baseline viral load and in kids you're talking about an order of magnitude higher."
So do you usually start children on more than three drugs anyway?
"I have started children on three drugs, but increasingly I tend to start with much more - for example, I had a newly-diagnosed two year old and started him on six drugs, he was very sick with a very high viral load and I wanted to get him controlled as quickly as I could. He had terrible problems with his bone marrow, his kidneys, his heart, his brain and everything was going wrong, so it was a very difficult hospitalisation for the mum who expected every day to be his last. I kept saying to her, 'It's very difficult but don't worry, stick with me, soon your child will be walking and you'll have an entirely different baby'. Well, I saw her in the clinic on Monday and she said to me, 'Boy were you right, he's not quite walking but he's crawling around, being naughty and keeping up with his one year old sister '. She was a totally different mum."
All your doses are BID so that gets round the school thing but still, do you have major issues with children and adherence?
"Adherence is a major problem, but our children and their families have a lot of problems. HIV-infected children are not born in a vacuum; HIV is not the only problem that they have in their lives. A lot of them are from families with (what's the PC term for this?), well they don't have a lot of financial resources, a lot of them are cared for by single parents or single grandparents who are taking care of a number of children."
"Also psychologically it's very difficult for a lot of women to have to wrestle with their toddlers (babies are slightly easier), especially on TID regimens, you can spend an hour wrestling with your child as they spit out their medicines. The formulations are horrible so you can't really blame the children. Plus there is the issue of confidentiality. Unlike a child with diabetes where everyone rallies round to be supportive, a lot of times you don't want your family or other people to know, so you have to take them into the bathroom and sneak in the pills. Some of the liquids have to be refrigerated, so what do you do when you're out on the holidays or on weekends? And a lot of these kids go to school early in the morning so, in addition to getting your three, four or five children dressed and fed and ready, you have to get a whole handful of pills down them - it's no fun."
"I would love for the schools to be able to give the meds and give the parents a break but because of confidentiality it's not usually possible. Children tend to fight the school much less than they fight their mums. Adherence for children is a big deal, and maybe one of the reasons we have less viral suppression in children."
And then, in adolescents?
"Not good. I just saw yesterday an eleven-year-old girl who had been suppressed for two years and now she's creeping up. When she was young, her mum insisted that she take her meds but now she's of a age where she takes, if not full responsibility but a fair amount of responsibility for taking her meds. Her mum gives her the meds but she may or may not take them. It's very hard for adolescents, they feel that its very unfair, they worry about their friends at school finding out, they feel very isolated because there aren't that many kids in the same situation and they really resent having to take the medicines. I sat down and graphed out what a viral load does, went through the dangers if it went over, told her 'Oh I wish I could take this away' "
Do you find it helpful when they begin to understand what a viral load is and about resistance etc?
"I think that it helps, what I do is measure out one millilitre of water and l show them that they have x number of copies in that amount of blood and I try to explain it that every time you take a pill it's like a bomb that will nuke it, I try to make it as concrete as I can. Sometimes it works sometimes, it doesn't, I continue to try and educate knowing that it sometimes falls on deaf ears. Part of being an adolescent is thinking you're invincible, and it's very hard when you feel well to think that there's a virus inside you that could kill you."
So are there any secrets to getting kids to take all those meds?
"For children, I've become more and more convinced that the thing to do is put in a gastrostomy tube. It can be a psychological barrier for some doctors, but we have no hesitation whatsoever putting in a central line which is much more invasive and has more complications. G-tubes are really not that bad, you can remove the tubing and they're just like an extra belly button, nobody needs to know and you don't need to worry about infection complications. If my child needed to take pills on a chronic basis I would insist on a G-tube. Even for the first child on our protocol - he was fine for the first three or four weeks, but as he started feeling better, he just refused to take his medicines or he would vomit them back up. So in two days the doctor put in a gastrostomy tube, it's much easier for him, and the mother loves it. He actually will take some of his pills by mouth, but especially the nelfinavir, he just hated it and they made him feel full. It's hard when you're having to take forty pills a day, twenty and twenty, for some kids it can take up to an hour at a time, you have to sit down and take all this stuff. He's OK with the d4T and the saquinavir, but the rest goes in the tube - you just pin them down, push the stuff in, then disconnect them, they go and play, and nobody thinks anything of it - takes five minutes. Most of our children who are that sick are small for their age anyway. So what I tell the mums to do, if anyone notices it in the summer time, is just tell them he doesn't really grow too well because he was premature (or whatever), and it's just to give them some food at night. I find that quite do-able and that way you save their mouths for feeding."
"For adolescents it's going to be a hard-sell, but frankly all these teenagers go around and pierce their belly-buttons (and everything else) - I think that if we could come up with a sexy button for them, maybe we could convince them it's the thing to do!"
I also noticed in your protocol that there is quite a span in age for the entry criteria with a high upper limit - from seven to twenty two years. Why these particular ages?
"I tried to be as inclusive as possible, for a lot of protocols thirteen or even eighteen is the upper limit. The reason that we chose seven as the minimum age though is that we felt that what they were undertaking was so aggressive that the kids should be of an age when they could, if not consent, assent. They should, know about their diagnosis, understand what they're doing and realize why they are doing it. I also wanted to avoid the very young children because then changes in the pharmacokinetics become an issue. I would love to have done this for adults, but I'm a paediatrician."
But by enrolling people up to twenty-two then aren't you treating some young adults anyhow?
"That's right. Even though I must say in terms of the interest that we've had in our protocol most of the kids have been around seven and eight. We are now actually on hold though, we can't enrol anybody, and we've had to amend our protocol because of the problems with the 5025 study."
What amendments have you made?
"What we have done is cut back on the d4T (it was double the standard recommended dose), but we have continued with the ddI. We have now instituted cut-off for management of asymptomatic elevations of amylase and lipase. We're following these children every month laboratory wise and clinically, We were always very acutely aware of the risk of pancreatitis and had a very detailed and conservative algorithm on how to manage signs and symptoms of pancreatitis, but after the unfortunate experience in the 5025 trial we have made it even more conservative. We are lowering the dose of the d4T as an amendment and going back to the FDA. So we have actually a bunch of kids waiting to enter in our protocol."
And I also noticed you are using hydroxyurea?
"Yes, so far, but we have to go back to all the regulatory people and of course have very vigilant management and appropriate interventions in cases of any complications. But you know hydroxyurea is used by kids with sickle cell."
So as soon as these doses are sorted out will you resume, it does seem important to know the outcome of this study?
"We are temporarily on hold but we look forward to resuming and seeing if this approach works. Our limited experience, and Montaner's data, would suggest that it does for many but not all. Our entry criteria are much more stringent than anyone else's; we are taking the sickest of the sick. I don't know of an adult protocol that has targeted people with a viral load of over 100,000, CD4 count of under 200 and who have failed as many drugs as we have. Some of the larger adult trials have included those, and the data would suggest that if you are NNRTI experienced you are much less likely to respond, but we'll see - it's really a phase 1 proof of principle trial. I know that even within paediatrics, a number of investigators have been moving towards five, six, seven drugs but this is to my knowledge the first children's protocol to look at that, but as you know in HIV, a lot of things happen off-study."
Do you use TDM (therapeutic drug level monitoring) to check their levels, this seems particularly important with children?
"I am fortunate enough that I have a pharmacologist who will do it here. It's not very available in the US, but I think it's essential with paediatrics, the levels change all the time. It needs to be done upfront though not only in a salvage setting."
Are you seeing instances of lipodystrophy with your kids and all the other stuff that we're concerned about with grown ups?
"Yes, we have seen and others have seen and reported that HIV-infected children on HAART can develop lipodystrophy and lipid abnormalities, and I've even heard of children developing diabetes. Within the Pediatric ACTG there is a protocol in development, to look at the metabolic effects and the effects on growth of HAART, so we'll know more once that data gets put together. Anecdotally it appears to be less than in adults, but it's hard to really say, there's so much more adult experience. I think that if we look at these groups we may be able to understand the basic pathophysiology because children are at a state of disequilibrium in terms of their endocrine systems so I think if we can ask the right questions and do the right studies, we may also get lots of answers for the adult population."
For the children that aren't growing well, do you find they catch up when they use HAART and have you found human growth hormone useful if they don't?
"As paediatricians we've always been focused on the whole area of failure to thrive, which has dramatically decreased with HAART, but even children who are virologically suppressed, not all of them grow. Is that because they had such an early insult and are unable to catch up or is it something ongoing? We haven't used human growth hormone here but I know of others that have, at UCLA they used it with a group of adolescents with lipodystrophy and they responded. Again there is a protocol in development to look at growth hormone and see if it does help. I have not had anyone with bad enough lipodystrophy or FTT that I would consider using it."
Treatment interruptions are becoming a popular current strategy for some adults, would you consider this for children, particularly if they were having difficulties with adherence?
"Yes, I have come to the conclusion that no drugs are better than intermittent drugs. At first I was rather scared taking them off, but I have kids off drugs with stable viral load and CD4 for sometime. But then I have another kid in hospital that was up and down on his meds and his mum admitted that he wasn't really taking them so we took him off. He was doing fine, for four for five months, then he shot up to a viral load of three million. I told his mum we have to treat him, he's only six so we got him in hospital and tried to teach him to take his pills and he tried really hard, but with the saquinavir soft gel caps (they're huge), he just couldn't swallow them so we put a tube in and we're waiting for him to respond. I think seeing the numbers rise like that made the mum really understand what we're up against."
And immune based therapies for kids?
"Oh yes and we have thought of adding IL2 to this protocol but, as it stands it's so complex already."
Do you use this very intensive multi-drug therapy more upfront and not just in a salvage setting?
"I would like to start mega-HAART in kids upfront. People are talking about the whole issue of a latent virus; people are talking about intensification but intensification with one or two drugs. If you look at the amount of radiation it takes to shrink a tumour - again I think we should learn from the oncologists and really aim for what's maximally tolerated, and then back off. And I think that this should be done in the setting of a protocol, so we can answer the question properly. I think part of what happens in HIV is that people jump on the bandwagon straight away, and I can understand why they do, I've done it myself. But there's a lot of toxicities associated with this, we need to answer this rigorously and scientifically; for this protocol, I could have done it here, called up a couple of my friends - it would have been a lot easier!"
Back to the 1007, and by way of a conclusion, describe simply the fundamental question that will be answered from this trial?
"That if we throw everything that we possibly, reasonably (reasonably in quotation marks that is) can at the virus in this very, very, very sick population with resistant virus, can we get anywhere? If we can't, then we learn that with our present drugs we cannot beat the virus down when it gets to this stage, then it's probably not worth subjecting to all the toxicities associated with this approach. We would be better off striving for a palliative approach. However, if we can show effect, it means that our weapons (drugs) can still be used to knock the virus down, even after it has won the first several rounds of the fight. I have no doubt that we will have to pay a price in terms of toxicity, so that every family will have to decide if the potential benefit is worth the risk of the toxicity. Hopefully this will provide children and their families with an additional option. Since we will be doing this trial in a controlled scientific manner, we will be able to provide these families with date on the potential risks and benefits."
What happens next then, can we then go to a maintenance regimen?
That's what we'll have to look at next - the daughter trial of 1007!
Protocol Summary (PACTG 1007)
Design: Multicentre, Phase 1, proof of concept protocol to evaluate the safety and tolerance of a multi-drug therapy administered at higher than standard doses for selected drugs.
Population: HIV-infected children and adolescents from age 7 years up to 22 years, with AIDS and prior exposure to multiple antiretroviral drugs.
Stratification: None
Regimen: Each of the following drugs will be administered for 48 weeks
| DRUG | DOSE |
Max single dose |
Max daily dose |
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Stavudine (d4T) |
2mg/kg BID | 80mg | 160mg |
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Didanosine (ddI) |
240mg/m2 QD | 400mg | 400mg |
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Lamivudine (3TC) |
8mg/kg BID | 300mg | 600mg |
| Nevirapine |
120mg/m2 QD x 14d 120mg/m2 BID | 200mg | 400mg |
|
Saquinavir (sgc) |
60mg/kg BID | 1200mg | 2400mg |
| Nelfinavir |
60-80mg/kg BID | 2000mg | 4000mg |
| Ritonavir |
450mg/m2 BID | 1200mg | 2400mg |
| Hydroxyurea |
10-20mg/kg QD | 1000mg | 1000mg |
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Support for children and carers is crucial with this approach. All patients are admitted to hospital (or clinical research centre) during the initial two weeks of the study. They then receive directly observed therapy (DOT) at home for an additional six weeks, eliminating adherence as a confounding variable (this will involve study personnel going to the child's house twice daily to observe the administration of the medication). It is expected that there will be a significant virological response during this time. It will also allow close observation of the child's caregivers and provide an opportunity for education and support. After this period adherence will be monitored with PACTG adherence modules, pill counts and regular therapeutic drug monitoring. Given the intensive and demanding nature of this protocol only highly-motivated parents/guardians and children who the site-care team believe can be adherent will be enrolled to this complex regimen. |
Physicians from the University of California, San Diego, in La Jolla, report what they believe is the first case of a child with HIV-related nephrotic syndrome who experienced a "...remarkable clinical and immunologic response" to triple antiretroviral therapy administered by gastrostomy tube.
"There is no consensus regarding the specific management of HIV-associated nephrotic syndrome," Dr Stephen A. Spector and associates explain in the December issue of Pediatrics. However, untreated nephrotic syndrome rapidly progresses to renal failure in up to 40% of HIV-infected children with this condition.
The patient was a 5-year-old African American girl who presented with advanced HIV infection. Her HIV-1 RNA levels exceeded 750,000 copies/mL and her CD4 cell count was 3 cells/µL. The child was chronically ill and her weight and height fell below the 5th percentile.
Recent symptoms included fever, cough, chest pain, vomiting, loose stools, abdominal distension, and anorexia. Laboratory findings confirmed nephrotic syndrome. Culture results revealed Streptococcus pneumoniae, but a good response was obtained with intravenous ceftriaxone.
The physicians placed a percutaneous gastrostomy tube to deliver supplemental nutrition, and triple antiretroviral therapy with stavudine, lamivudine and nelfinavir was administered via this route.
After 21 months of triple therapy, "...her weight and height had increased to the 50th and 10th percentile respectively, and she had complete resolution of her nephrotic syndrome," they report. In addition, the child's "...CD4+ cell count increased to 1116 cells per microlitre and her viral load has remained undetectable."
Dr Spector's group points out that it is not clear if "...the presence of a gastrostomy tube contributed to the excellent response because of improved compliance." However, they believe that it "...warrants systematic evaluation."
Ref: Pediatrics 1999;104:1394-1396. Source: Reuters Health
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The use of a gastrostomy tube by these doctors and in the PACTG study outlined previously is novel and obviously worthy of further investigation. As dosing is often difficult in children and PK's generally understudied we see no reason why TDM should not be routinely used in the management of antiretrovirals for infants and children. |
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HIV DRUGS IN THE NEW MILLENIUM
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Forget power outages and computer crashes. HIV is the real millennium bug -- the one that will persist long after the lights have come back on. Sadly, there won't be a gift-wrapped surprise to stop the virus in its tracks under anybody's Christmas tree in 1999. For the time being, the ultimate miracle on 34th Street -- an actual cure for HIV -- is still just an entry on our wish list. Protease inhibitors simply aren't enough to rid the body of a virus that wedges itself into just about every nook and cranny of the immune system. Some critics even argue that we've lost valuable time these past three years by putting all our eggs, meaning research dollars, in the protease drug basket while ignoring other promising leads. But almost two decades of drug research have taught us valuable lessons about how and when to use existing therapies. They've also opened the door to exciting new crossover fields, yielding clues about other illnesses such as cancer, sexually-transmitted diseases, and autoimmune disorders.
Today, with so many targets and strategies to stop HIV and so many mix-and-match therapies, it's hard to keep pace with the field. As it stands, a determined if not-so-merry band of drug developers and researchers are racing off in different directions, some focusing on improved versions of existing therapies, others intent on exploring new chinks in HIV's armour. So what's the next best thing? Actually, there are several, from novel compounds to improved formulations and strategic recombinations of existing drugs to immune-boosting vaccines. Is any one perfect? Of course not. But even with their flaws, there's ample reason to keep hoping and working on a major breakthrough.
That said, veteran researchers and activists temper their praise of today's drugs with a rueful sense of lessons learned the hard way. "To the extent that protease inhibitors were heralded as the end of AIDS, we were too optimistic," says Spencer Cox, a firebrand activist with New York's Treatment Action Group, choosing his words carefully. "To the extent that they caused a revolution in the way people were treated-that ain't beans." [Ed. ..."that ain't no small feat?"]
Summing up what many now feel, he adds, "We weren't too optimistic about the drugs; we were too optimistic about what they could do."
Stab In The Dark
The AIDS epidemic has taken such a toll and become such a given to most people that the pre-AIDS years sometimes feel like the distant past. But in the early 1980s, when the first cases of rare pneumonia began turning up in gay men in the United States, no one knew the virus existed. It took several years before HIV was identified as a member of the family of human retroviruses, newcomers on the viral scene. It later became clear that HIV is also a member of the subfamily of so-called slow viruses, or lentiviruses. Even now, fundamental aspects of HIV's nature remain mysterious. But in the early years, it was a virtual stab in the dark.
Back then, scientists scavenged the dusty shelves of drugs discarded by cancer researchers and combed the relatively young field of retroviral research for potential targets that might disarm HIV. It was a makeshift discovery effort guided by trial and error, hobbled by their scant knowledge of the virus and a lack of precedent about how to tackle a fast-moving, lethal epidemic with such a devastating scope. Add to that the stigma still attached to AIDS in many places, and government foot-dragging on funding for research.
These factors seriously hampered efforts to develop drugs but helped spawn a powerful activist movement that has continued to push for better and cheaper drugs-faster. "When you really think about it, this is the first virus that we've had any effective antiviral drugs against. I mean, there are one or two drugs out there for herpes and so forth, but on the whole we have never really had good drugs," says Neal Nathanson, M.D., director of the Office of AIDS Research at the National Institutes of Health. "A lot of good science happened in the early years, but I don't think anyone had a grand plan," says Jules Levin, executive director of the National AIDS Treatment Advocacy Project (NATAP), an activist who keeps close tabs on HIV research. "It's partially luck, partially hit-and-miss." The big difference is that now it takes a fraction of the time to fail or succeed.
Copycat Drugs
Ten years ago, scientists had what amounted to a child's sketch of HIV-and one could count the number of realistic targets for anti-HIV drugs on one hand. The main target was an enzyme called reverse transcriptase (RT) that acts a little like a Xerox machine, allowing the virus to make copies of itself inside the cell. The family tree of anti-HIV drugs reflects this simplicity: AZT, a recycled cancer drug that blocks reverse transcriptase, was the first drug the Food and Drug Administration approved for HIV in lightning speed in March 1987. All the approved drugs that followed have fallen into three categories, or classes: nucleoside reverse transcriptase inhibitors (NRTIs) like AZT; nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors that block HIV's exit from cells (see chart). There are also a handful of unapproved drugs in different categories, including Preveon, a nucleotide inhibitor of reverse transcriptase (NTRTI), and hydroxyurea, another dusted-off cancer drug. But that still leaves only two basic targets, RT and protease.
To date, each new class of drugs has buoyed hopes and, in one way or another, dashed them. In 1993, a large-scale, three-year drug trial, the Concorde study, proved what many had feared: AZT by itself (monotherapy) didn't slow the deadly course of AIDS. That finding was followed by reports of drug resistance to monotherapy and, later, the development of multiple drug-resistant strains of the virus. Meanwhile, people on therapies have had to cope with different side effects associated with each drug. Metabolic problems and liver disease linked to long-term use of highly active antiretroviral therapy (HAART) have forced some people to reconsider the benefit versus risk of these therapies. As if that weren't all, the latest roadblock concerns HIV latency, or the discovery of small but durable reservoirs of HIV inside dormant immune cells of people on HAART therapy that can't be reached with current drugs. These reservoirs could last up to 60 years, say scientists-in other words, a lifetime.
Needed: Simpler, Low-Cost Drugs
Today the treatment community is unanimous about one thing: The next generation of drugs must be more powerful and easier to take. They should also improve the problems associated with the present generation of drugs, such as resistance, dosing, absorption, and bioavailability (the active part of a drug that's available to fight the virus). "There is little reason to develop a novel drug unless it can be taken once or twice daily," says Steven Deeks, M.D., a leading HIV physician in San Francisco who has documented alarming rates of HAART failure among his patients, frequently because they have a hard time sticking to the complicated drug schedules.
Looking at the problem of resistance, it's now known that unless the virus is virtually eliminated from the blood-again, an unlikely prospect-it's only a matter of time before a viral mutant emerges that's resistant to therapy. Current estimates are that the virus mutates once each time it copies itself-up to one billion times a day. "It's like going to Las Vegas," says Thomas Merigan, M.D., director of the Center for AIDS Research at Stanford University. "HIV just keeps spinning its bases [its genetic building blocks], looking for a jackpot."
Now that we know more about HIV's building blocks, a more focused approach is being taken in drug development. About two years ago, the National Cancer Institute moved away from the time-honoured method of random screening-an educated version of the trial-and-error method-to a targeted-discovery approach that builds on each new insight we gain about the virus and how it causes disease. "We now have the luxury of drugs that work and viral structures that are known," says Jonathan Kagan, chief of Drug Development and Clinical Sciences at the National Institutes of Health, who's hopeful that the shift will speed the discovery effort.
New Ally: The Immune System
What else is there to be optimistic about? Well, for starters, the crude sketch of HIV that yielded the first drug targets has given way to a more detailed portrait and multiple targets on the virus, as well as ways to help protect cells from infection. The early assumption that HIV takes a wrecking ball and totals the immune system has also turned out to be not quite right.
Instead, new studies show that, with some help from HAART, the body's immune resources can be restored and even boosted to possibly control the virus. That suggests an important role for novel immune therapies and even therapeutic vaccines. Long the stepsister of virology, immunology has stepped into the spotlight of HIV research, and scientists talk excitedly of "using the immune system as a drug," a concept put forth by Stefano Vella, M.D., a keynote speaker at the Sixth Conference on Retroviruses and Opportunistic Infections in Chicago earlier this year. Vella was referring to a paradigm shift that has taken place in our collective thinking about HIV-away from the goal of total eradication of the virus and on to HIV remission, or long-term control of HIV.
Historic Steps
To understand where we stand today, it helps to look back to the targets and therapies that have been tried so far. For every drug that's made it to market, hundreds of leads have failed to live up to their promise. Few people today recall AL-721, Peptide T, or soluble CD4, except the survivors of a period when, given the odds, it made more sense to try something than nothing. But as author and AIDS chronicler Mirko Grmek wrote so sagely in 1988, "All these recent efforts must await their own historian." In fact, drugs like Peptide T may yet have a role to play. A protein, Peptide T aims to block fusion, another critical step in HIV's life cycle, as does the new hotshot drug T-20. Ditto for soluble CD4, which could interfere with HIV's ability to infect cells, as do another promising class of compounds called coreceptor blockers. If you squint your eyes right when it comes to HIV drugs, it looks like history sometimes repeats -- and improves -- itself.
If the HAART era was the time when pharmaceuticals changed the way we think about HIV, the next millennium may be the time when HIV changes, once and for all, the way we think about drug development. The whirlwind wedding with protease drugs taught us that too-rapid drug approval comes with a human price-side effects and drug failure-and solidified the leap-before-you-look-too-hard school of thought. "It's not necessarily being done haphazardly, but when you approve drugs quickly, it takes longer to understand them," says activist Levin, summing up one of the trade-offs of accelerated drug approval.
So where does that leave us? With a host of experimental compounds that come, as new drugs do, with a range of caveats and wait-and-see promises. We've come a long way, it's true-and we've learned some surprising and disheartening truths about drugs in the existing classes. From where we stand now, between the hopelessness of the early 1980s and the dampened enthusiasm of what may soon be called the post-HAART era, it looks as if the best is yet to come. Of course, that will greatly depend on whether and how quickly the government and drug companies invest in promising but risky new approaches, and whether activists push them to do so.
Here, then, is a look at the family tree of anti-HIV drugs, with its budding branches.
Nukes: Firstborn Problems
No one said it was easy being a pioneer. When AZT broke ground in the field of antiretroviral therapy, it was almost inevitable that the drug would become a lightning rod for critiques and bitter disappointment. As the first drug to receive FDA approval for HIV, it was used alone (as monotherapy) for more than four years and served as a template for similar drugs in its class. "Nukes," or NRTIs like AZT, ddI, d4T, 3TC, and newcomer Ziagen, compete with cellular building blocks for places on HIV's DNA assembly line, acting like rogue Scrabble pieces, creating crucial "misspellings" that make it harder for the virus to reproduce itself. Using nukes as monotherapy, or in two-drug combinations, slowed the course of HIV-but only just. People continued to get sick, with no sign of the immune reconstitution that is now, in the HAART era, an important index of drug success. Although nukes have become important parts of any combination regimen, none, except perhaps Ziagen, pack the punch of a protease inhibitor.
Is it the drugs or the way they were used? A little of both. It's now known that no drug can be used as monotherapy, or resistance to the drug may quickly develop and prevent using other drugs in the same class. Since most nukes have been around longer than other drugs, they're more likely to have been used alone, or misused in suboptimal combinations. This long, chequered past means that many people may carry nuke-resistant viruses. But used correctly, the drugs still have potential, perhaps even as cornerstones of a nonprotease regimen using newer nukes Ziagen and pipeline candidates DOTC [Ed - dOTC development is currently suspended] and DAPD. New studies show 3-nuke combos work as well as protease cocktails to stop HIV [Ed - Caution, see comments at end of article]. As Merigan emphasizes, even with the oldest class of drugs, there's plenty to learn. "Abacavir [Ziagen] is a pretty good compound," he says. "We're not used to using it yet; there may be better ways to do it."
On the downside the oldest class faces new questions about long-term safety. In recent months, evidence has suggested that the drugs' dupe pieces of genetic material interfere with its normal ability to divide, which could lead to cancer "The recent NRTI discussion underscores the fact that long-term toxicities have not been well defined," says physician Deeks, adding a word of caution about nukes.
Nonnukes: Looking Good
If there is a Cinderella class of anti-HIV drugs, it may well be "nonnukes," or NNRTIs. With the recent approval of Sustiva, and more potent candidates in the pipeline, some experts have dubbed NNRTIs "the class whose time has come." Like nukes, they inhibit reverse transcription but with a different mode of action. NNRTIs fit themselves directly over important regions in the reverse transcriptase enzyme. Some NNRTIs also have potency that rivals that of protease inhibitors (PIs), and given the side effects of PIs, there's interest in using NNRTIs as the basis of first-line regimens. For researchers, the biggest question is how best to use these new tools. "Nonnukes are good drugs," says Merigan. "We really need to know whether to use them as first- or second-line therapy." This also means figuring out the best way to use NNRTIs in combination with other drugs. Are two NNRTIs in a single regimen better than one? Will the two drugs compete and actually cancel out their potency?
Once again, the biggest stumbling block is resistance. A single viral mutation called K103N can create cross-resistance to most drugs in this class. Newer drugs are designed to work against viruses with this specific mutation. But there are also reports of new mutations arising from nuke-nonnuke combinations and concerns about as yet unknown long-term effects. For now, nonnukes are a valuable option, both in protease-sparing combos for people just starting therapy and as salvage options further down the line.
Protease Inhibitors: A Dead End?
Leader of the pack or sitting duck? With their overwhelmingly positive effect on the course of HIV disease, protease inhibitors have done more to change how people think about HIV than any other class of drugs. Still, most people are far from starry-eyed over these four-year-old meds, and if you listen closely, you may even hear sacrilegious whispers asking: Does this class have a long-term future?
The answer, for now, is yes. In the next year or two, new and better protease inhibitors are likely to get FDA approval. Some, like tipranavir (see sidebar), may even be an option for those with PI-resistant viruses. Many advocates believe that the drug companies are feeling the pressure to produce something new. "Part of what shapes this is market forces," say TAG member Cox. "We won't see a lot of me-too PIs because people can't or won't use them." Others argue that it's easier and cheaper for drug companies to modify PIs than pursue other, riskier avenues, so we should expect yet more slightly different third-generation me-too PIs.
Like reverse transcriptase inhibitors, protease drugs came about in large part because their target was familiar, which also made them financially attractive to drug companies. Protease, or proteolytic enzymes, work like a fleet of miniature chemical chainsaws that cut up and package proteins found throughout the body. The protease active in HIV is called aspartic protease, an enzyme that puts the finishing touch on newborn particles, or virions, as they are being launched off the surface of an infected cell.
When researchers went looking for new HIV targets, they already knew how to target a different type of protease using a class of drugs called renin inhibitors, so it wasn't that much of a step to block HIV protease. This familiarity and the surprising potency of the drugs fuelled their rapid approval. "This was extremely important [to drug companies] from a drug development standpoint," explains Carl Dieffenbach, associate director of the Basic Sciences Program at the National Institute of Allergy and Infectious Diseases (NIAID).
By now, the headlines trumpeting the success of protease inhibitors are old news, replaced by a growing concern over their toxicity. There's no doubt the drugs work to stop HIV, even in people who are quite ill, but at what price? Liver failure? A heart attack? As scientists try to understand what causes PI side effects, they're also learning from early mistakes. The first protease trials simply added the drug to existing combinations-a guaranteed recipe for resistance. "There's been a lot of inappropriate use of protease inhibitors," says Eugene Sun, M.D., head of antiviral ventures at Abbott Laboratories. "We've learned how not to use them."
Drug delivery is another major stumbling block for protease inhibitors. To arrive at a viral target, all drugs move through a protein-rich thicket of plasma, the liquid component of blood. Proteins are sticky substances that latch on to other compounds and impair their function. Early PIs acted like protein sponges and were nearly useless in fighting HIV. Although reformulations have greatly improved PI delivery, they've left us with large pills taken by the handful to achieve the necessary dosage. Even with constant revisions and updates, the drugs continue to have a major impact on the liver and kidneys, and this is likely to take its toll. "The current drugs are not great," says Abbott's Sun bluntly.
There's also been debate about whether this late-stage attack on the virus is an ideal strategy. PIs attack newly formed virus particles, or virions, as they're budding off infected cells. The drugs don't block the creation of genetic mutants of the virus, which occurs during an earlier stage. This may give the virus an edge over protease inhibitors. On the other hand, some scientists believe that PIs could have unexpected positive effects on the immune system that go beyond fighting the virus. "It could be that the immune system chews up dead virions and responds to them," suggests Dieffenbach of NIAID. "You may be getting an immune boost from them."
AprŹs Y2K, What Now?
Too much has been learned about the virus and its ability to hide and mutate to rest easy with what's in today's medicine chest. An alternative strategy involves designing drugs that interact with infected cells as opposed to the actual virus. "We've come full circle," says Amy Patrick, Ph.D., head of virology at Agouron Pharmaceuticals. "Early antiviral drug-design efforts paralleled research on treating cancer, and then focused on finding new virus-specific targets. Now we're back to asking, how can we inhibit the host-gene functions?" New techniques mine our knowledge of cells, genes, and viral assembly. Since many of these novel agents go after different targets than those used by existing drugs, they should be active against today's drug-resistant virus.
Rising Stars: Coreceptor blockers
One hot area of drug research is aimed at ways of preventing HIV from entering cells. To understand what that means, think of a lock on a door. Coreceptor blockers bind to sites, or doorways, on the cell surface that the virus uses for attachment and entry. In other words, they jam the lock. The two coreceptors receiving the most attention are called CCR-5 and CXCR4. Initial interest in these compounds grew when it was discovered that some people who had a genetic defect in CCR-5 appeared to be fully or partly resistant to HIV. Since that time, other doorways have been discovered. Some scientists worry, however, that blocking one door-CCR-5-will only lead HIV to choose another-CXCR4. Unfortunately, the latter is usually associated with more virulent strains of the virus. At least 50 percent of people who progress to AIDS eventually develop viruses that use CXCR4. However, many experts, including coreceptor researcher John Moore of the Aaron Diamond AIDS Research Center, believe that we may be overestimating the risk of receptor-switching, particularly if a strong CCR-5 blocker is found. "It's a gut reaction that this is going to happen," he says. "Maybe the gut's not quite right." Moore and others theorize that there may actually be a negative selection pressure that prevents the emergence of viruses that use the CXCR4 doorway.
There's also the possibility that the virus could bypass both coreceptors and adapt to using other docking sites all together. It's also unclear how toxic a combo of agents that block the CCR-5 and CXCR4 doorways might be. At this year's insider-track Gordon Drug Conference in California, coreceptor blockers were all the buzz-until things got serious. "Drug companies were talking, [all] excited, and then it was like an iron door came down," says NIAID's Dieffenbach, a conference cochair. "The race is on."
The Dark Horse
This winter a novel anti-HIV approach that developers are calling "protein therapy" enjoyed 15 minutes of fame-perhaps a sign of things to come, perhaps a flash in the pan. Also known as the "trojan horse" strategy, this approach uses innovative packaging to smuggle proteins that are up to 200 times bigger than current drugs across the cell membrane. If coreceptor blockers fiddle with locks and keys, protein therapy aims to walk through cellular walls carrying its antiviral weapon. The advantage to larger protein molecules is that they are much more specific, zeroing in on a single reaction or target with precision. In this case, a team led by Steven Dowdy, an ebullient Howard Hughes professor at Washington University in St. Louis, has chosen Caspase-3, a protein that responds to a specific stage in HIV replication by triggering cell suicide.
"If you've never read any of my papers, the first response would be '...and if pigs had wings,'" says Dowdy. Indeed, some researchers point out that since Caspase-3 only recognizes actively infected cells, there will always be virus particles that escape before cell suicide takes place-sort of like closing the barn door after the horses (or pigs) have escaped. "Current HIV strategy is basically trying to put the brakes on a train that's going downhill," says Dowdy. "Why not exploit the viral protease enzyme and allow it to roll down the tracks and crash?" He adds that, theoretically, protein therapy could be used to fight hepatitis C, malaria, and other infectious agents that use a protease as part of their lifecycle. Caspase-3 is still in animal trials.
Arming Cells
Long favoured as the ultimate solution to many illnesses, including heart disease and cancer, gene therapy offers the tantalizing possibility of arming a cell for life by changing its genetic makeup. So far, gene therapies aimed at making cells immune to HIV have been slow to develop. The biggest problem is delivery. It's almost impossible to get genes into 100 percent of cells at exactly the same concentration, the condition required for effective gene therapy. Julianna Lisziewicz of the Research Institute for Genetic and Human Therapy has spent years working in the field. "I think the only way this problem can be solved is if we can put genes into stem cells," she says, referring to a cell type that is often called "the mother of all cells" because it gives birth to the many specialized cells of the body. "And even with that, we're still not efficient enough." Lisziewicz is more hopeful about gene therapies that help boost immune response to the virus and could potentially serve as a vaccine strategy.
The Late Bloomer
In the great pageant of medicinal breakthroughs, integrase has been, well, a no-show. Long hailed as the next big thing in anti-HIV drugs, integrase inhibitors have been long in coming, in part because scientists were stymied by the enzyme's tendency to bind to itself and form solid crystals that hopelessly obscured its structure. Finally, this year a team of scientists at Merck Laboratories figured out the three essential steps that the integrase enzyme performs. This major breakthrough was then offset by the nearly simultaneous realization that the most effective time to block integrase is when it's bound to viral DNA. Before they can develop a drug that might stop integrase from working, researchers will have to get an exact 3-D image of the tight-fisted grip that forms between the convoluted, pocked, shape-shifting protein and the viral DNA. Daria Hazuda, a Merck chemist who has spent the last five years working on integrase, says it's extremely difficult to figure out the structure of the enzyme when it's bound to the substrate [viral DNA]. "That's one of the things that keeps me up at night," sighs Hazuda.
The Swat Team
Another promising area of research involves HIV genes such as nef, rev, tat, gag, pol, env, vpr, vif, and vpu that could play a key role in creating vaccines. These are also the names of the "accessory" proteins they code for. The proteins act as viral Green Berets with specialized missions that go beyond assembly and packaging, and appear to be toxic to cells at surprisingly low concentrations. Nef- and tat-deleted viruses are being tested in vaccine studies. They can trigger an immune response to the virus without causing disease. But so far, no candidate seems entirely safe. Robert Gallo, M.D., codiscoverer of HIV, is especially excited about the tat gene, which he hopes to use in a vaccine. In lab studies, antibodies to tat block HIV replication. Human studies using a tat toxoid look promising. We may still see the development of drugs targeting specific genes or gene products, particularly as new research and better tests improve our understanding of these behind-the-scenes players.
Hide and Seek
With so many areas of HIV infection still a mystery, treatment activists and researchers are also paying close attention to aspects of the disease that current therapies fail to address. For starters, there's latent infection, the phenomenon that originally stole the thunder from the promise of a cure. It's now known that HIV ducks below the immune-system radar by stowing away in dormant cell reservoirs of lymphoid tissue and protected sites like the brain. Now a new theory, put forth by virus hunter Ashley Haase at the University of Minnesota, suggests that the virus may spread between nondividing cells, perhaps using a molecular underground railroad to make its way from one apparently locked house to another. If this is the case, then there may be whole realms of viral activity that will have to be mapped and blocked by as-yet-undiscovered drugs.
Even without cell-to-cell spread, latent viral reservoirs remain a critical obstacle to long-term control of the virus. To effectively target these reservoirs with drugs, some researchers believe they need to understand them better. But to do that, they have to be able to find them. Right now, we lack a simple, sensitive screening technique to detect these hidden viral reservoirs.
Today researchers are testing Interleukin-2, an immune booster, to see if it can flush out virus from the latent reservoir. Other interleukins are also being investigated as potential therapies.
Future Gambles
The big question mark on the horizon is whether immune-based therapies and vaccines could be used as complementary approaches to antiretroviral drugs. At last count 36 vaccines were being tested in U.S. clinical trials, some for both therapeutic and preventive uses. This means they could help HIV-infected and uninfected people. Several DNA-based vaccines look especially good. In small studies of primates, they induced protective cellular-immune responses to genetically engineered SHIV viruses made of an HIV envelope and a core of the simian immunodeficiency virus. These vaccines don't eradicate the virus but contain active infection. As such, they represent a working model for HIV remission.
Over at the Yerkes Primate Research Center in Atlanta, Harriet Robinson, M.D., found that a DNA vaccine combined with a fowl pox, or bird virus booster, could elicit cellular-immune or CTL (cytotoxic T-lymphocyte) responses that protected macaques for more than 62 weeks. The vaccine significantly reduced the level of virus replication. After vaccination, the macaques were repeatedly exposed to or "challenged" with virus, and each time they mounted a "memory" T-cell response. This suggests, at least theoretically, that such a vaccine might contain rebounding viruses in people on therapy who have undetectable virus levels. The same thinking applies to the sexily named Co-X-Gene, a "naked DNA" prime-boost vaccine, now entering human trials in Australia. Studies by Stephen Kent, M.D., show the Co-X-Gene protected macaques against active infection. Best of all, the vaccine is very cheap-just a few pennies per shot-and doesn't require refrigeration, so it's ideal for use in the developing world.
There's also interest in Remune, also known as the Salk Immunogen, which is being tested in combination with antiretroviral regimens in human trials. Early studies showed Remune can boost HIV-specific immune "lymphoproliferative responses" (LPR) that appear crucial to controlling HIV. But a big Remune study involving 2,500 people was just ended because the drug didn't seem to help (or hurt). Researchers are looking to see what happens to people on therapy who receive Remune and later abandon therapy altogether. The hope is that the vaccine will help control any outbreak of the virus.
High Stakes Futures
Discovering new drugs is only half the battle. A chorus of global activists reminds us that progress must extend beyond the lab bench. New discoveries will be worthless if they can't be used by the people who need them most -- growing numbers of women, children, and the poor. Today's imperfect array of life-saving HIV therapies are available to a mere 10 percent of the world's HIV-positive population, which numbers tens of millions. Power may flicker as the world rolls over into Y2K, but for everyone affected by the AIDS epidemic, it will also be time to see if new lights are turned on at the end of a very dark tunnel.
Source: HIVPlus - January 2000 NUMBER SIX http://ww2.aegis.com/pubs/hivplus/2000/jan/updates/drugs.html
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This article provides a useful summary of the state of HIV treatments at the close of the 20th Century. We would however express caution over the view that triple nucleoside analogue combinations "...work as well as protease inhibitors." There is currently no evidence to support this statement, and indeed evidence in subjects with starting viral loads above 100,000 copies/mL that triple nucleoside regimens are inferior in potency (even those containing abacavir). This evidence prevented such regimens being recommended as initial therapy for na•ve subjects in both the recent British (BHIVA), US and French treatment guidelines. Additional caution is warranted over fears that triple nucleoside regimens may also lead to multidrug resistance across the class of nucleoside analogues through inadequate viral suppression and/or treatment failure (see IDSA report in this issue of DrFax). |
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ANTIRETROVIRALS
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People with HIV failing on existing protease inhibitor treatment will have the chance to obtain the new protease inhibitor ABT-378 (also known as lopinavir or by the trade name Aluviran) within weeks, the French drug regulatory agency announced yesterday.
Under a scheme called Autorisation temporaire d'utilisation (ATU), the French government can compel companies to make an anti-retroviral drug available before it has completed clinical trials or received a European license.
Under the ATU negotiated with Abbott Laboratories, individuals with viral load greater than 10,000 copies and a CD4 below 200 who are failing on, or intolerant to currently licensed protease inhibitors, will be able to obtain ABT-378.
In October Abbott Laboratories was attacked by the European AIDS Treatment Group for failing to make progress in establishing a meaningful expanded access programme in Europe, despite six months of lobbying by European activists. Expanded access plans for other European countries remain uncertain despite the French announcement.
One clinical study has shown that approximately two thirds of individuals with rising viral load after their first PI failure achieved undetectable viral load within six months of switching to ABT-378. Data on the efficacy of the drug in individuals with multi-PI experience is still lacking.
Source: http://www.aidsmap.com
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ABT-378 is urgently awaited by patients in the UK and the rest of Europe who now have no further treatment options and deteriorating clinical status. Although the activity of ABT-378 in salvage settings is uncertain it is truly inhuman to delay access for those with no other rational choices. Abbott assures us that drug is available and that European regulatory authorities are willing to import. The block appears to be in getting the drug out of the U.S. The FDA will not currently allow export of this drug for use outside of clinical trial settings (ie. for named patient use in Europe). If this FDA position is not reconsidered then expanded access studies will be the only route to access in Europe, these will be many months away due to the lengthy procedures involved in both local or centralised ethics approval and will only provide for drug supply to those treatment centres willing to engage in the process. Abbott, however, must also shoulder responsibility for this miserable state of affairs. Expanded access studies should have been in place months ago in the eventuality of not being able to obtain export for named patient use. European treatment advocates discussed early availability of this drug with Abbott in the US earlier this year and it is shameful that we are still attempting to overcome blocks to access almost a full year later. |
Gilead has announced that it has begun enrolling patients in a multinational Phase III clinical trial of its investigational agent tenofovir disoproxil fumarate (tenofovir DF, PMPA) for the treatment of human immunodeficiency virus (HIV) infection. The study is designed to enrol a total of 600 patients at nearly 70 sites in the United States, Europe and Australia. This trial is the first in a series of pivotal studies to define the role of tenofovir DF in the management of HIV disease. Tenofovir DF is a nucleotide analogue formulated as a pill taken once daily as part of combination antiretroviral regimens.
Study Design
The Phase III study (GS 907) is a 48-week randomised, double-blind trial that will evaluate the safety and antiviral activity (as assessed by the Roche Amplicor(R) Monitor(TM) Ultrasensitive Test) of tenofovir DF as a component of combination antiretroviral regimens in treatment-experienced patients. The study is designed to enrol up to 600 patients infected with HIV who have HIV RNA levels greater than/equal to 400 copies/mL and less than/equal to 10,000 copies/mL and who have maintained a stable antiretroviral regimen (comprised of not more than three antiretroviral agents) for at least eight weeks prior to enrolment.
Based on preliminary efficacy and safety results from the dose ranging Phase II trial (Study 902) of tenofovir DF, patients enrolling in Study 907 will be randomised (2:1) to receive a dose of tenofovir DF 300 mg or placebo in addition to their existing regimens. Following randomisation, patients will be encouraged to maintain their antiretroviral regimen for 24 weeks of blinded dosing. After 24 weeks, patients receiving tenofovir DF 300 mg may make changes in their background antiretroviral therapy and patients assigned to receive placebo will crossover to open-label active tenofovir DF for the remainder of the 48 week study period.
Phase II Preliminary Results
In September 1999, Gilead presented preliminary results from a randomised, double-blind Phase II clinical trial (Study 902) evaluating the safety and efficacy of once-daily tenofovir DF when added to a stable background antiretroviral regimen in treatment-experienced HIV patients. The 48-week dose-ranging study enrolled 189 treatment-experienced patients at 22 U.S. sites who were on a stable antiretroviral regimen for at least 8 weeks prior to entering the study. Patients were randomised to receive one of three tenofovir DF doses (300 mg, 150 mg or 75 mg) or placebo (2:2:2:1) in addition to their existing treatment regimen. At week 24, all placebo patients were switched to the tenofovir DF 300 mg treatment arm.
The primary efficacy analysis was conducted on data compiled through the 24 week placebo-controlled period. Anti-HIV activity was observed in all three active treatment arms, with the greatest reduction in viral load (-0.75 log10 copies/mL at week 24) observed in the 300 mg dosing arm. Treatment with tenofovir DF was well tolerated at all three dose levels for up to 48 weeks. The incidence of serious adverse events was similar among all study arms and was reported in 7% of patients in the 300 mg dose group compared with 11% of patients in the placebo group; drug-related nephrotoxicity was not observed. As of November 30, 1999, 77 (41 percent) of the 189 patients enrolled in Study 902 have completed 48 weeks of dosing and have rolled over into open label extended dosing.
Enrolment Information for Gilead's Tenofovir DF Studies
To address the need for new treatment options among treatment-experienced patients, Gilead has initiated a limited compassionate access protocol for tenofovir DF (Study 908) designed to enrol up to 300 patients in the United States. Patients and physicians who would like more information about enrolment in either Study 907 or 908 of tenofovir DF for the potential treatment of HIV/AIDS may call the AIDS Clinical Trials Information System (ACTIS) at 1-800-TRIALS-A or Gilead Sciences Medical Information at 1-800-GILEAD-5 (1-800-445-3235).
Source: Gilead Sciences Press Release
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Compassionate access to PMPA in Europe is urgently needed. Gilead have now merged with Nexstar pharmaceuticals who will ensure a European presence. Let us hope they can avoid the shameful delays associated with "compassionate" access to ABT-378. |
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OBSTETRICS
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HIV infection in pregnant women is not a reason to do an elective caesarean section routinely, according to Karen P. Beckerman, MD, Director of the Bay Area Perinatal AIDS Center (BAPAC) at UCSF. Dr. Beckerman believes that HAART (highly active antiretroviral therapy) suppresses the maternal HIV viral load such that an elective caesarean is not necessarily indicated, if the only reason is HIV infection. Dr. Beckerman has followed approximately 80 HIV positive pregnant women through delivery and after birth of their babies. Among those 80 or so women, only three caesarean sections were performed. Dr. Beckerman reported that there have only been three HIV infected infants in San Francisco in the last approximately three years. Two of the three mothers did not know they were HIV positive and were not tested by their private physicians. The third mother had only one prenatal visit and delivered her baby severely premature after only 25 weeks of pregnancy. All the other women delivered HIV negative babies due to anti-HIV therapy taken during pregnancy (most took HAART) and following the standard "076" protocol. (That includes intravenous [IV] Retrovir [zidovudine] during labour and six weeks of oral Retrovir for the newborn infant.) Ever since the announcement at the 1998 12th World AIDS Conference in Geneva that combination anti-HIV therapy during pregnancy plus an elective caesarean section could decrease mother-to-newborn HIV transmission to less than 3%, many HIV pregnant women choose to have an elective "C" section. Caesarean section rates among HIV positive pregnant women at most centres in North America and Europe now are very high. Dr. Beckerman said that when she asks her HIV positive pregnant patients the reasons why they want a caesarean section, the reason usually is not to decrease the risk of transmitting HIV to their babies. Reasons they give include fear of pain during labour and convenience.
Dr. Beckerman cautions that standard indications for an emergency "C" section during labour should still be followed (foetal distress, others). (Note that an elective caesarean section is planned for approximately the 38th week of pregnancy, before labour or rupture of [womb] membranes ["bag of waters broken"]. Dr. Beckerman noted the higher rate of complications from caesarean section (infection, others, approximately 15%) in HIV positive women, when compared to HIV negative women.
Dr. Beckerman will routinely start anti-HIV therapy at twelve weeks of pregnancy, and not the 14th week, as is standard '076' protocol. Dr. Beckerman also obtains an HIV RNA viral load test weekly in her HIV positive patients taking anti-HIV therapy. Several studies have shown that the greatest risk for HIV transmission from mother-to-newborn is mother's HIV viral load.
Dr. Beckerman also commented that some of her patients are taking IV Retrovir and oral Viramune (nevirapine) during labour. (A major study from Uganda was published this year indicating that one 200 mg dose of Viramune taken by an HIV positive mother during labour and one dose by the newborn by age three days decreases HIV transmission by 50%, even when the mothers breastfeed their babies.-HIVNET 012)
Reference: Beckerman KP. Vertical transmission. 14th Annual Medical Management of AIDS: a Comprehensive Review of HIV Management. Sponsored by the University of California at San Francisco and the University of Utah. December 2-4, 1999; San Francisco, California. Source: http://www.hivandhepatitis.com/
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HIV DRUG RESISTANCE DATA AT IDSA
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Several presentations at The 37th Annual Meeting of the Infectious Diseases Society of America (IDSA 99) offered data on the HIV genotypes observed in patients failing antiretroviral therapy. I will report on several abstracts that focused on resistance to the nucleoside reverse transcriptase inhibitors.
Resistance to Abacavir
Until recently there has been little in vivo data reporting the mutations associated with resistance to abacavir. Understanding abacavir resistance is important in order to learn what options exist in the nucleoside reverse transcriptase inhibitor class for patients who fail on abacavir. Two presentations from the Glaxo Wellcome virology group described mutations in abacavir recipients who had previous experience with nucleoside reverse transcriptase inhibitors, and in a group of patients who were antiretroviral na•ve before experiencing virologic failure on a two drug combination with abacavir and one of several protease inhibitors.
One report by Ross et al. [1], described the experience of 87 patients who stopped their mono- or dual nucleoside reverse transcriptase inhibitor therapy, switched to the combination of zidovudine, lamivudine, and abacavir., and subsequently developed virologic failure. 56 patients maintained a viral load < 400 copies/mL after 48 weeks of treatment. Prior to switching to ZDV/3TC/ABC, 30 (54%) of these patients had a 184V mutation associated with 3TC resistance and 29 (52%) had a mutation associated with a thymidine analogue (ZDV or d4T). Fifteen patients experienced virologic failure, ten of whom had genotypes available at baseline and at the time of treatment failure for comparison. 80% of these patients with treatment failure had a 184V mutation at baseline and 70% had at least one mutation associated with resistance to a thymidine analogue. The baseline viral load was higher in those patients with experienced treatment failure compared to those who had a durable response, 21,476 copies/mL versus 853 copies/mL. Decreases in viral load following the switch to the triple regimen were similar in patients with and without virus with the codon 184V mutation.
One of the 15 patients experiencing virologic failure had wild type virus at the time of viral load rebound. Four patients rebounded with only a codon 184V mutation, though additional mutations associated with resistance to ZDV accumulated over time in two patients as they continued on therapy. The remainder had an assortment of ZDV-associated mutations together with the 184V mutation. The most commonly encountered mutations were M41L (7 patients), D67N (6), T69D/N (2), K70R (4), and T215Y/F (8). One patient developed a L74V mutation after 48 weeks of therapy that is associated with ddI resistance; this mutation can also be selected by abacavir. Phenotyping of virus from eight patients showed reduced susceptibility to abacavir in 6 patients, to 3TC in 7, and to ZDV in 4.
What can we conclude from all of this? First, abacavir is active in patients with virus that has the 184V mutation associated with resistance to 3TC. Patients who fail on a ZDV/3TC/ABC combination will likely have virus resistant to all three drugs, and therefore, should probably have a completely different combination used in the next regimen. As yet, we still do not know what options exist in the nucleoside reverse transcriptase inhibitor class for patients who fail on this triple combination (they may not have many or any). Lastly, I think this data provides a strong case for the use of abacavir to intensify antiretroviral therapy in patients with low viral loads that have not reached undetectable levels, or perhaps in patients with are experiencing early treatment failure with low viral loads.
Another report by Ross with a different group of colleagues [2] described the genotypic profile of virus from 17 of the 18 patients (out of 74 patients originally treated) failing treatment with a two-drug combination of abacavir plus indinavir, nelfinavir, saquinavir, ritonavir, or amprenavir. No mutations associated with resistance to abacavir was present at baseline. Five patients had mutations associated with abacavir resistance at the time of virologic failure -- either M184V or K65R. Six patients had mutations in the protease cleavage region, and ten had polymorphisms in the protease gene that are commonly seen in patients failing on a protease inhibitor.
This study demonstrates that resistance to abacavir does not develop rapidly, as is the case with 3TC or any of the non-nucleoside reverse transcriptase inhibitors. In addition, since the 184V mutation can be selected by abacavir (the mutation associated with 3TC resistance), one has to wonder if abacavir should ever be given in a combination without 3TC.
Resistance in START I and START II
Many reports have described genotypic changes of virus in patients failing on combinations that include ZDV and 3TC. There are far fewer reports of the resistance profiles of patients with viral load rebounds on combinations that don't include 3TC. Trip Gulick reported on the genotypic and phenotypic changes of virus from patients experiencing virologic failure in the START I and II trials [3], two trials that compared different dual nucleoside regimens in triple drug combinations with indinavir (ZDV + 3TC versus d4T + 3TC in START I, and ZDV + 3TC versus d4T + ddI in START II). Only three of 61 patients had baseline mutations (one RT 184M - 3TC mutation; one RT 41L - ZDV mutation; and one PR 10I - indinavir mutation.
Twelve of 34 patients with virologic failure on ZDV/3TC/IDV had wild type genotype and phenotype. Twenty-one patients developed a RT M184V/M mutation that was most often associated with a > 100-fold loss of phenotypic sensitivity to 3TC. Two of these patients also had single mutations to indinavir (PR V82A in one case and PR L10V in another), though isolates remained phenotypically sensitive to indinavir. One patient had a PR L10L/I mutation that remained phenotypically sensitive to indinavir.
Thirteen patients had virologic failure on d4T/3TC/IDV. Five rebounded with virus that a wild type genotype and phenotype. One patient had a RT M41L mutation at baseline and had no new mutations at the time of failure. Seven patients had the RT M184V/M mutation and phenotypic resistance to 3TC. One of these patients also had the PR L10V mutation.
Fourteen patients had virologic failure on d4T/ddI/IDV. Interestingly, eight of these patients had no genotypic changes and had phenotypically wild type virus. Two patients had baseline PR L10I/V mutations, developed no new mutations at the time of rebound, and had phenotypically wild type virus. One patient had RT V75V/M mutant virus that was phenotypically wild type. Two patients had PR V82A mutations associated with resistance to indinavir, though the virus remained phenotypically sensitive to indinavir. Lastly, one patient had virus with a RT D67D/N mutation and PR M46M/L, PR I54I/V, and V82A mutations that was 6-fold less sensitive to indinavir. Thus, all patients had virus that was phenotypically sensitive to d4T and ddI at the time of virologic rebound.
This study confirms that patients on a 3TC- and protease inhibitor-inclusive combination will likely have only 3TC genotypic and phenotypic resistance when first experiencing virologic failure. It also suggests that it may be hard for the virus to develop resistance to d4T and ddI when those two drugs are used in combination. The high proportion of patients who rebounded with wild type virus in all treatment arms is difficult to explain. These patients may have been poorly adherent to medications and were, in effect, on a suboptimally active combination. It is possible that a minority population of resistant virus was present but not detected. Alternatively, there may be pharmacokinetic or cellular mechanisms that result in virologic failure in some cases. Whether a greater number of treatment options remain for patients failing on a d4T/ddI combination than d4T/3TC or ZDV/3TC combinations is a question that will only be resolved with the strategic antiretroviral trials that are underway.
Novel Codon Deletions
Several groups have described nucleotide insertions at codon 69 in the reverse transcriptase encoding region of the HIV genome that is associated with the development of virus that is broadly resistant to all of the nucleoside reverse transcriptase inhibitors. At this meeting, Ross and colleagues [4] identified four patients with three-nucleotide deletions at RT codons 67, 69, and 70 . (Abstract 365) These were always in association with other, more commonly described mutations in RT. All of these patients had extensive treatment histories including at least three nucleoside reverse transcriptase inhibitors. Virus with the codon 69 was phenotypically resistant to ZDV, 3TC, and abacavir, but sensitive to d4T, ddC, and ddI. Virus with the codon 70 deletion was resistant to all of the nucleotide reverse transcriptase inhibitors. Of the two patients with codon 67 deletions, one viral isolate was phenotypically resistant to only zidovudine, the other was sensitive only to d4T. To understand the role the codon 67 deletion mutation has on virus independent of other mutations, a recombinant virus with the codon 67 deletion was constructed. This virus retained phenotypic sensitivity to all of the reverse transcriptase inhibitors. Therefore, unlike the codon 69 and 70 deletions, the codon 67 deletion is not associated with phenotypically altered virus.
The clinical significance of this report is uncertain. We do not know how commonly these codon deletions occur. If present, they may be missed by the currently available genotyping assays, illustrating another potential limitation of these tests. This report does underscore the fact that new paths for the virus to develop resistance to the currently available drugs continue to be described.
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The pattern of resistance mutations observed with failure of the abacavir containing triple combination represent another form of nucleoside reverse transcriptase inhibitor multi-drug resistant HIV. These subjects were pretreated with nucleoside analogues before exposure to abacavir. However, it would be reasonable to assume that the potential for this pattern of resistance may still exist, even in drug na•ve patients, when triple nucleoside analogue regimens result in inadequate virological control in poorly monitored settings. Salvaging the failure of such regimens will prove problematic. A double protease inhibitor plus NNRTI regimen would be the logical next line but the durability of this approach without nucleoside support is unknown. |