Medical Consultant
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ANTIRETROVIRALS
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Currently approved anti-HIV drug combinations are remarkably effective at reducing the amount of HIV in many patients to undetectable blood levels. For most, the clinical benefits add up to a healthier, longer life. Yet two studies in a recent edition of the New England Journal of Medicine demonstrate that, as good as these drugs are at suppressing HIV, other approaches likely will be needed to knock out the last vestiges of the virus.
"These findings are not unexpected," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which provided major support for both studies. "The data add to other recent findings indicating that it may be impossible to eradicate HIV from the body with currently approved antiretroviral therapy. What all these studies underscore is the pressing need to develop more effective, less toxic medications that can be used over the long term to suppress HIV, as well as novel strategies to then purge residual virus from the body and boost the immune system. In this regard, many important leads are being pursued by investigators in government, academia and industry."
The era of highly active antiretroviral therapy, or HAART, began about three years ago when the first protease inhibitors were incorporated into multi-drug HIV treatment regimens that included older anti-HIV drugs such as AZT. Hopes that the drugs could "cure" AIDS were raised when some patients experienced dramatic drops in the level of HIV in their plasma. More sophisticated studies, however, subsequently turned up evidence that some virus survived the therapy by hiding in certain cells and tissues.
The NEJM studies were conducted by separate groups of investigators from the Aaron Diamond AIDS Research Center in New York, led by Linqui Zhang, Ph.D., and David Ho, M.D., and from Northwestern University Medical School in Chicago, led by Manohar Furtado, Ph.D., and Steven Wolinsky, M.D. Both groups focused attention on the reservoir of HIV found within circulating blood cells of patients who had successfully suppressed HIV in their plasma with HAART. The patients were taking various combinations of three to four anti-HIV drugs, including protease inhibitors. With strict adherence to HAART, all had kept HIV below detectable levels for approximately two to three years.
Although evidence has been accumulating that HAART may not wipe out all traces of the virus, it has been unclear what feeds the low-level residual infection. One unanswered question, for example, was whether HAART completely stops viral replication. If not, evidence of viral replication could mean a small but unending source of replicating HIV exists to replenish the reservoir.
To look for evidence of ongoing viral replication, Dr. Zhang and his colleagues studied four sequential cell samples taken from each of eight patients. They examined latently infected cells for changes in the genetic makeup of HIV from sample to sample, which could indicate ongoing replication of HIV. The cells from six patients showed few if any such changes. Over time, however, significant variations in the genetic makeup of HIV's coat protein appeared in cells taken from the other two patients. The changes, the researchers note in their paper, are "likely due to ongoing residual replication, albeit at an exceedingly low level." Studies of various tissue samples and body fluids from one of the two patients confirmed residual HIV replication in cells taken from his lymph nodes, tonsils and gastrointestinal tract.
The Northwestern University group examined at least five sequential blood samples taken from each of five men who also had used HAART to keep HIV below measurable levels for 20 months or more. To investigate the characteristics of the HIV reservoir in these men, they measured changes in the concentrations of HIV DNA and viral RNA in cells over time. They observed that after an initial rapid decline, the levels stabilised, indicating that viral replication persisted. This plateau, they say, suggests that the rate at which cells become infected with newly made virus is approximately equal to the rate at which older infected cells die. "Unless this quasi-steady state eventually disappears with longer periods of therapy or can be overcome by the use of more potent therapies or alternative approaches that block the potential spread of virus within tissues, HIV-1 may never be eradicated," they write.
"...it is sobering to realise," note Dr. Zhang and his colleagues, "that the so-called highly active antiretroviral therapy is actually not always active enough. As we strive to eradicate HIV-1 infection or induce a remission, we must focus on the possibility of further intensifying antiretroviral treatment, even though current therapies are already toxic, costly and complex."
One bright spot in this picture, says Carl Dieffenbach, Ph.D., associate director of the Basic Sciences Program in NIAID's Division of AIDS, is that the technologies developed by these investigators provide "new tools, so that if we ever have a patient in whom it appears the virus has been eradicated, we'll be able to verify that." This ability will become increasingly important, he says, as new and improved drugs shrink the latent reservoir of HIV even further.
References:
1. L Zhang, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. The New England Journal of Medicine 340(21):1605-13 (1999).
2. M Furtado, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. The New England Journal of Medicine 340(21):1614-22 (1999).
3. R Pomerantz. Residual HIV-1 disease in the era of highly active antiretroviral therapy. The New England Journal of Medicine 340(21):1672-74.
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In an accompanying editorial Roger Pomerantz of Thomas Jefferson Medical College notes that..." These and other recent studies have allowed us to approach rationally the issue of residual HIV-1 disease during seemingly effective highly active antiretroviral therapy. This viral reservoir may need to be eradicated if one is ever to achieve virologic cure in even a select number of HIV-1-infected patients, although immunologic control of viral replication may still be possible in certain patients. Further compounding the problem is the fact that there may also be sites, such as the central nervous system, retina, and testes, in which viral replication is partially shielded from antiretroviral agents by a blood-tissue barrier." "Comprehensive therapy for HIV-1 disease can be viewed in a way that is similar to treatment for cancer. Highly active antiretroviral therapy, which suppresses high-level viral replication, can be considered induction therapy. To continue the analogy, once remission is accomplished, the therapeutic approach may have to be altered to focus on attacking residual disease. Intensification therapy to block low-level replication of virus despite apparently effective highly active antiretroviral therapy may be the next critical step. To detect such low-level replication will require valid diagnostic tests that are practical for use in large numbers of HIV-1-infected patients and not just in specialised research laboratories." "Recent data show that viral inhibition in vivo is correlated with inhibiting plasma levels of HIV-1 RNA to below 20 copies per millilitre, rather than to the cut-off value of either 400 to 500 copies per millilitre used in routine assays or 50 copies per millilitre used in ultrasensitive assays. It is thus important to remember that "close may not count" in clinical retrovirology when the goal is the eradication of a virus." "In addition to administering intensification therapy, it may be necessary to stimulate truly latently infected cells and infected cells that may have transcriptionally active but translationally inactive virus. Stimulatory therapy with interleukin-2 may be beneficial in at least some patients by depleting viral reservoirs. Novel approaches should also be assessed, including treatment with hydroxyurea, described by Lisziewicz et al. in this issue of the Journal, which acts by inhibiting reverse transcription of HIV-1 in resting CD4+ T lymphocytes or potentially by reducing the number of CD4+ T lymphocytes (thereby decreasing the number of cellular prey for the viral predator). As in oncology, it may be important in some patients to combine treatment approaches, such as inhibiting low-level viral replication and stimulating latently infected cells to express virus, which could then be killed by cytotoxic T lymphocytes or allowed to die as a result of virally induced cytopathogenicity. This complementary approach may also result in long-term remissions in many patients even if it cannot completely eradicate the virus in all patients." Perhaps Highly Active Antiretroviral Therapy (HAART) would be better be described as Moderately Active Antiretroviral Therapy (MAART). We have always assumed that one cause of viral escape was ongoing viral replication - in reality the lymph nodes themselves are a viral sanctuary.
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DuPont Pharmaceuticals announced on June 1st that the European Commission has granted full marketing authorisation for its anti-HIV drug, efavirenz (Sustiva() in Europe. Efavirenz is the first once-daily anti-HIV drug to receive full marketing authorisation in Europe in antiviral combination treatment of HIV-1 infected adults, adolescents and children three years of age and older.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Resistant virus emerges rapidly when NNRTIs are administered as monotherapy; therefore, efavirenz must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Efavirenz therapy should always be initiated in combination with at least one other antiretroviral agent to which the patient has not been previously exposed.
Safety data from clinical trials show efavirenz is generally well tolerated. The most significant adverse events associated with efavirenz therapy are nervous system symptoms, which are reported in approximately half of patients (e.g., dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming). The discontinuation rate for nervous system symptoms in clinical trials was 2.6 percent. These symptoms occur early in treatment and generally resolve within a few weeks. Rarely, patients have more serious side effects that may affect mood or ability to think clearly. Mild to moderate skin rash was reported in approximately one out of four patients. The incidence of severe rash was less than 1 percent. The discontinuation rate for rash in clinical trials was 1.7 percent.
Efavirenz was approved by the Canadian Health Protection Branch on March 19, 1999 and by the U.S. Food and Drug Administration (FDA) on September 17, 1998 for the treatment of HIV-1 infection in combination with other antiretroviral agents. This indication is based on analyses of plasma HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV-RNA with efavirenz.
Further information on efavirenz is available in the United Kingdom on the Internet at: http://www.dupontpharma.co.uk
Source: DuPont Pharmaceuticals press release.
Bristol-Myers Squibb announced on June 3rd that the 15 Member States of the European Union have reached a mutual recognition agreement on the once daily dosing of didanosine (ddI, Videx(r)) for the treatment of HIV. The first once daily nucleoside reverse transcriptase inhibitor (NRTI) will be marketed under the established trade name VIDEX(r). This mutual recognition may now be implemented by each member state through national marketing authorisations. The approval of once daily ddI is based upon a submission of an expert scientific report; a summary of previously published clinical studies and the results of clinical trials. The expert report reviewed the scientific basis for once daily dosing of ddI. The summary of clinical studies concluded that ddI dosed once daily is as safe and effective as ddI dosed twice daily in suppressing viral load and increasing CD4 cell count. The summary's conclusions were further confirmed by the results of two randomised clinical studies comparing once daily dosing with twice daily dosing of ddI.
The European AIDS Treatment Group puts easier-to-take drug regimens near the top of their priorities, applauding the EMEA's decision to accept ddI (Videx) once-a-day labelling. The data used to confirm ddI's usefulness in a once-a-day dosing scheme has existed for some years, and the EATG is happy that industry (Bristol-Myers Squibb) as well as the authorities have seen the need to approve scientifically what was happening anecdotally for quite a while - people were taking ddI successfully once-a-day. The pharmacokinetic as well as clinical data regarding once-a-day administration was reported as far back as 1994. Although once-a-day regimens may not necessarily improve adherence/compliance, it could be useful in the case of ddI, for it's current difficult manner of administration that makes it an ordeal "better to have to do only once-a-day", according to one ddI user in Poland. "As ddI must be taken on an empty stomach, as well as distanced from some other HIV medications, having only one such period per day is much more helpful to us who take ddI", reflects another EATG member from Holland. One problem with once-a-day regimens is that if a dose is forgotten you will have a longer "window" period in which the virus will possibly not be under control. And in the few studies that have been done concerning convenience of dosing, there is not much difference between the numbers of adherent people taking once-a-day regimens (70% max) Vs people on a combination antiretroviral regimen (also 70% max).
The makers of ddI have also announced that shortly there will be a new enteric-coated capsule formula of ddI.
Source: Bristol-Myers Squibb Press Release & EATG Press Release.
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A 200 mg per tablet formulation of ddI is currently available from Bristol-Myers Squibb on a named patient basis in the UK. This allows for once daily dosing (2 x 200mg) with half of the antacid buffer contained in 4 x 100mg. Many patients find the buffer the most difficult part of ddI administration to tolerate. Food restrictions still apply with this reduced buffer formulation. Physician enquiries should be made to Alpa Vaghela at BMS on 0181 754 3788, or to Paul Slade, Medical Advisor, BMS on 0181 754 3600. |
For the first time in the history of HIV infection and AIDS, European physicians, virologists and activists are joining their forces to generate management guidelines for HIV treatment. The focus is use of resistance testing in the treatment of HIV infection. The panel's mission is to generate guidelines for drug resistance testing as a part of HIV treatment and make recommendations to ensure the implementation of these guidelines in all European countries. The first report will be communicated in October at the European AIDS Conference in Lisbon. The panel will continue to meet on a regular basis to update the guidelines as the European situation is monitored within the framework of evolving treatment strategies.
Drug resistance diminishes the potency of anti-HIV products in patients whose viruses have acquired it, and represents one of the main challenges for the medical community. Once HIV has mutated, the available anti-HIV products may no longer keep the virus suppressed. Additionally, resistance to one compound may cause cross-resistance to drugs the patient has never been exposed to. This limits future therapeutic options since patients may not be able to benefit from any other treatment. Public health may be impaired by the dissemination of resistant strains in the newly infected population. Transmission of multi-drug resistant strains has been observed in Europe; for these patients, initial treatment options are also severely limited. In other words: the uncontrolled development of HIV resistance means a setback of the fight against AIDS.
Assays to detect and measure drug resistance have been developed and these may help clinicians and virologists better monitor treatments, by identifying the genetic changes in the virus (called genotyping) and by measuring the resistance level (called phenotyping). For these new techniques to be used optimally, identification of the situations where they could be most useful and a large quality control system are vital. As always, when a new medical technology is integrated into daily practice, clinicians need to be trained to interpret the results. More research is necessary, but already some conclusions can be drawn which can help doctors make evidence-based decisions regarding anti-HIV treatment.
To make the management of the HIV infection more beneficial to the patient and more cost effective to society, European clinicians, virologists and representatives of the HIV affected and infected community decided to join forces by creating the very first panel of experts. This panel has the objective to recommend not only how to use these new assays, but also to identify steps necessary to collect information on how best to use them. This European panel of experts will assess the current HIV drug resistance status in Europe and generate guidelines for resistance testing as a part of overall HIV treatment monitoring strategy. Technical issues may limit the use of resistance assays and guidelines to establish a reliable measurement are mandatory. In addition to translation and dissemination, the panel report will be presented to the EU and health ministries. Cost implications (moneys saved by not prescribing drugs to which a patient's virus population is resistant) will be analysed. The panel will present the report to EU and health ministries. The initiative was started by Veronica Miller and Joep Lange, facilitated by the European AIDS Treatment Group (EATG) and the European AIDS Clinical Society (EACS).
The panel has an academic core, consisting of Veronica Miller (chair), Joep Lange (co-chair) Nathan Clumeck (EACS), François Houyez (EATG), M Andreoni,D. Banheghi, A Broekhuizen, F Brun-Vezinet, R Camacho, F Clavel, K de Clerk, B Clotet, R Colebunders, N Dedes, P Gargalianos, J Gerstoft, W Hall, A Hatzakis, R Hoetelmans, C Katlama, C Loveday, J Lundgren, K Mansinho, F Mulcahy, M Opravil, L Perrin, JC Schmit, A Sönnerborg, V Soriano, L Stahle, S Staszewski, A Vandamme, S Vella, M Youle. To ensure that the panel objectives are met, the panel will draw heavily on the expertise of: G Biondi, C Boucher, G de Schrijver, K Hertogs, B Larder, A Phillips, D Pillay, R Schuurman, A Williams.
Source: EATG Press Release
Jules Leven of The National AIDS Treatment Advocacy Project (NATAP, USA) reports amprenavir (APV) interaction data from Glaxo Wellcome presented at a community forum. At this meeting Steve Piscatelli from the NIH reported, for the first time publicly, PK data on combining ritonavir (RTV) 200 mg bid or nelfinavir (NFV) at full dose (1250 mg bid) with amprenavir and efavirenz (EFV) in a salvage study. The actual clinical data was not available yet but is expected to be presented possibly by ICAAC. However, the pharmacokinetics (PK) were discussed. EFV significantly reduces APV blood levels when combined at full doses. However, when combining full dose APV and full dose EFV with 200 mg bid RTV -- APV AUC doubled, APV Cmin increased 5-7 fold and APV Cmax remained the same. This means that RTV prevented the reduced APV blood levels when using EFV with APV.
When combining 1250 mg nelfinavir with full doses of APV and EFV the same effects were seen but it appears as though additional nelfinavir diarrhoea may result and the pill count is significant.
Source: Jules Levin, NATAP NEWS
In a letter to the editor, Kathleen Melbourne, of Coastal Medical in Rhode Island, details the case of a patient whose HIV medication regimen was disrupted by his religious beliefs. The 44-year-old Egyptian male was noted to have missed one-third of his prescribed indinavir doses. Investigation revealed that the man had ceased use of the drug over Ramadan, when individuals of the Islamic faith fast between sunrise and sunset, or about 12 hours each day. The patient explained that while Islams with chronic diseases are not required to fast, many devout individuals do so anyway and do not take their medications during that time. Melbourne notes that such abstinence can have very serious clinical consequences and suggests that medical personnel be aware of how a patient's religious beliefs might affect their health practices.
Ref: Journal of the Association of Nurses in AIDS Care (05/99-06/99) Vol. 10, No. 3, P. 99; Melbourne, Kathleen M. Source: CDC HIV/STD/TB Prevention News Update
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IMMUNOTHERAPY
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Pools of latently infected CD4 T cells are proving the greatest stumbling block to eradicating HIV. These latently infected CD4 cells can exist for a long time, and it has been postulated that it would require up to 60 years of antiretroviral therapy to destroy all traces of HIV. Some cytokines, such as interleukin (Il-2), can force expression of latently infected, resting CD4 cells. Researchers investigated the efficacy of Il-2 in conjunction with highly active antiretroviral therapy (HAART). The non-randomised, cross-sectional study followed 14 patients receiving HAART plus intermittent Il-2 and 12 patients receiving HAART alone. The plasma viraemia level of all patients was less than 50 copies of HIV RNA per mL plasma. Resting CD4 T cells were isolated using a column-based purification technique. Investigators found a marked decrease of latently infected, resting CD4 T cells in patients who received Il-2 along with HAART, as compared to those who received HAART by itself. In addition, the number of infectious units per million cells was markedly lower in patients receiving IL-2 and HAART treatment. Investigators note that the lymphoid tissues of the subjects proved an especially good environment for virus replication.
Ref: Nature Medicine (06/99) Vol. 5, No. 6, P. 651; Chun, Tae-Wook; Engel, Delphine; Mizell, Stephanie B.; et al. Source: CDC HIV/STD/TB Prevention News Update
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The use of IL-2 in patients receiving antiretroviral therapy must weigh the potential benefits against increased risk of viral breakthrough. Clearly antiretroviral therapy should be highly not partially active before IL-2 is introduced. |
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OPINION
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Mark Harrington, Treatment Action Group (TAG), New York City.
With the prolonged demise of HIV eradication hypotheses and the growing appreciation of the various unpleasant realities of lifelong HAART, the issue of the optimal time to initiate treatment with antiretroviral therapy in chronically HIV-infected individuals is enjoying something of a renaissance. While the "Concorde" of triple cocktail combinations may still be a ways off (yet, unsurprisingly, less far fetched in the U.K. than in the states), AIDS experts in the U.S. have at least recently allowed themselves to consider the possibility that "hitting it early" just might not be the irreproachable paradigm it was once believed to be. At last month's AIDS Update in San Francisco, TAG's Mark Harrington was invited to share his thoughts on this increasingly timely topic. A transcription of Mark's "When to start?" remarks appears below.
The question "When to start?" is one of the most important unanswered questions facing AIDS research. Therefore, it would seem likely that some of the best, smartest AIDS researchers would be trying to answer this question. Unfortunately, for a variety of reasons, this is not the case. Unfortunately, therefore, we do not have much more hard evidence than we did three years ago [at the time HAART was introduced] about the best time to start antiretroviral therapy.
My talk will have five sections:
1. What do we know now?
2. Why don't we know more?
3. The reasons for starting early are theoretical.
4. The reasons for starting later are practical.
5. What can we do to answer the question?
What Do We Know Now?
We know that viral load and CD4 levels predict the rate of progression and time to AIDS. Higher viral load equals faster progression. Lower CD4 count means a shorter time to AIDS. We know this from MACS [Multicenter AIDS Cohort Study] data published by John Mellors in 1996 and 1997. However, the MACS data included only men. In addition, we know from newer data that women progress with a somewhat lower viral load then men. However, the difference was not judged great enough to warrant a change in Public Health Service (PHS) guidelines at this time.
We know from several randomised, controlled trials with clinical endpoints (ACTG 175, CPCRA 015, Delta) that if you start with a CD4 count below 350/mm3, it's better to start with two nucleoside analogues (ZDV+ddI or ZDV+ddC) or ddI alone than to start with ZDV alone. We know that this approach actually slows time to AIDS and reduces mortality when compared with ZDV monotherapy over several years of follow-up.
We know from ACTG 320 that if you take an ZDV-experienced person with a CD4 count below 200/mm3, adding 3TC and indinavir, your chance of developing AIDS or dying is half that of those who added only 3TC -- for the period of time studied.
We also know from Abbott's pivotal licensing study that if you give ritonavir to people with a CD4 count below 100/mm3 who are already on one or two nucleoside analogues, the rate of AIDS illness and death is also halved, at least in the immediate term. We know from retrospective, observational studies carried out in the U.S., Canada, France and elsewhere in the developed world, that AIDS and death rates have plummeted since the introduction and widespread use of HAART.
It's important to note, however, that most of the deaths which have been averted have been among people whose CD4 counts were already quite low when HAART was introduced. For example, the twice-published studies of Frank Palella included only people whose CD4 counts were below 100/mm3 at baseline. Among this group, mortality has dropped by more than half since 1996. But we have no reliable clinical evidence that starting any kind of antiretroviral therapy with a CD4 count over 350 cells/mm3 prolongs either health or life. We have no reliable clinical evidence that starting HAART with a CD4 count over 200 cells/mm3 prolongs health or life. Thus, if we restricted our data set to randomised, controlled clinical trials, we would have no compelling reason to put two thirds of the HIV infected population -- those with a CD4 count over 350 -- on treatment at this time.
The Health and Human Services (HHS) Guidelines Panel (of which TAG's Spencer Cox and Mark Harrington are members) evaded the issue of "When to start" by saying that, in the asymptomatic population, the decision to start treatment should be made by the patient and physician taking into account the risk of progression as measured by viral load and CD4, the patient's willingness to undertake therapy, and other factors. "Treat or observe" for the group with a CD4 count below 500/mm3 or a viral load higher than 10,000-20,000 copies/mL. "Observe or treat" for the group with higher CD4 counts or lower viral load.
Of course, experts and blue ribbon panels have been wrong before. In 1990, after the results of ACTG 019 were released, The Public Health Service (PHS) recommended the use of early ZDV for all people with CD4 counts below 500/mm3. This was refuted by the Concorde study in 1993. In the early 1990s, experts commonly recommended the addition of ddC (or less commonly ddI) to a failing ZDV regimen. This approach was disproved by ACTG 155 in 1993 and by later studies.
As late as 1995, many "experts" were adding new protease inhibitors -- most commonly Roche's hard capsule saquinavir (Invirase), as it was the first to be approved -- to failing nucleoside regimens. By 1996, it was clear that this was the wrong strategy for starting a protease inhibitor (it should, instead, be given with a new background of nucleoside analogues) and that Invirase, the weakest drug of its class, predisposed people to developing resistance to other, stronger protease inhibitors.
Of course, since no one is carrying out definitive large, long-term randomised controlled trials with clinical endpoints of different starting times, we are unlikely to witness the direct refutation of the current paradigm -- although it is likely to be displaced by new developments.
Why Don't We Know More?
What are some of the reasons, or excuses, why we don't know more about when to start, and why more research isn't being done to answer this question? First, the field is rapidly changing. New drugs and new concepts are constantly emerging.
Secondly, answering this question conclusively would take several years and several thousand patients. However, hundreds of thousands of "early" patients (for the purposes of this talk, defined as those with a CD4 count over 350-500/mm3) are already on HAART, and we don't know if it's helping them in the long run. Moreover, no one flinches from a several thousand patient study to validate new approaches with new mechanisms of action, e.g., interleukin-2 (Proleukin) or the Salk Remune HIV immunogen. Why shouldn't we undertake one which has such profound public health and cost implications?
Third, doctors like giving pills. Fourth, drug companies like selling pills. Fifth, the short-term benefits of HAART in advanced disease are dramatic. Sixth, the large NIH-funded clinical trials networks are busy struggling to be refunded. The AIDS Clinical Trails Group (ACTG) and the Community Programs for Clinical Research on AIDS (CPCRA) are both up for renewal in the year 2000, and they're too busy worrying about whether they'll be refunded to launch an ambitious trial such as "When to start."
The ACTG claims it lacks the patients. The CPCRA claims it lacks the resources. The NIH, which funds them both, claims it lacks the authority to make the networks do the study. The drug companies lack the incentive, and so won't supply drug for such a study. The insurance companies and HMOs, which do have an incentive to have this question answered, seem indifferent to the potential gold mine of data (and possible savings) which such a study could provide. Finally, some of the best and brightest AIDS researchers lack the patients and the resources and are more interested in biological mechanisms than in large public health studies. Obviously, this is an untenable and unacceptable collective evasion of responsibility.
The Reasons for Starting Early are Theoretical.
Some might object that such drug holidays might encourage the development of drug-resistant HIV. So far, evidence from both Franco Lori's group and from the COMET study does not support this objection (see Lori et al., "Intermittent drug therapy increases the time to HIV rebound in humans and induces the control of SIV after treatment interruption in monkeys," late breaker abstract LB5, Sixth Retrovirus Conference, and Neumann et al., "HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated therapy," AIDS 13(6):677-83, April 1999)
In the COMET Study, 10 antiretroviral-naive patients initiated therapy with zidovudine, lamivudine, and indinavir for 28 days, followed by interruption of all drugs for 28 days and then reintroduction of the same regimen. No new resistance mutations developed during the study. The authors conclude that a 1-month interruption of all drugs in a HAART regimen does not adversely affect the virologic efficacy of the same regimen once reinitiated (Neumann 1999).
The Reasons for Starting Later are Practical.
Adherence to protease inhibitors (PIs) was assessed electronically in 84 subjects at two sites using MEMScaps. Baseline CD4 counts ranged from <50 cells/mm3 >500 and baseline viral load from <400 copies/ml to >100,000. At three months, a highly significant association was found between adherence and virologic suppression (p=0.00001). 81% of subjects with >95% adherence had complete viral suppression compared to 64% with 90-95% adherence, 50% with 80-90% adherence, 25% with 70-80% adherence and 6% with <70% adherence. (Paterson et al., "How much adherence is enough? A prospective study of adherence to protease inhibitor therapy using MEMSCaps," abstract 92, Sixth Retrovirus Conference 1999).
What strategies do activists have to encourage researchers to find out what is the best time to start antiretroviral therapy? We are encouraging NIH funded researchers and others to:
Early or Late
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| The Theory | The Reality |
| Starting early preserves immune function. | Immune function does not appear to become significantly compromised until CD4+ T-helper cells fall below the 300-350 cells/mm3 mark. |
| Starting early forestalls the development of resistance. | Under conditions of less than complete suppression of viral replication, selective drug pressure on HIV by early drug therapy actually facilitates the development of drug resistance. |
| Starting early prevents widespread dissemination of the infection and thus shortens the time required for eventual eradication. | There is no evidence that this is true and some evidence that the exact opposite is closer to being the case. (In a 1998 study at Johns Hopkins University, individuals with the most advanced HIV disease prior to initiation of HAART showed the fewest number of persistently infected memory T-cells after treatment.) |
| Starting early spares or preserves the HIV-specific T-cell subsets. | Because potent antiretroviral therapy dramatically reduces the quantity of circulating virus, HIV-specific immune responses virtually disappear on HAART due to the relative absence of antigen. |
Arguments for Delayed Antiretroviral Therapy
Source: TAGline June '99.
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IN BRIEF
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A substantial reversal of CD4 cell depletion in HIV-infected patients may be possible with a long-term reduction in viral load of at least 3 log, according to findings reported in the May 28th issue of AIDS.
The study "...provides some of the strongest evidence yet available for the direct causal relationship between HIV replication and CD4 lymphocyte depletion, which is pertinent to the debate surrounding the causes of CD4 cell depletion and its reversal with therapy," Dr. Andrew Phillips, of the Royal Free and University College Medical School in London, UK, and multinational colleagues say in the journal.
The investigators monitored CD4 cell counts and plasma HIV RNA levels in 154 HIV-infected patients beginning treatment with indinavir-containing regimens. Measurements were performed every 4 weeks for a period of 72 weeks. Overall, mean CD4 cell counts increased by 143/µL during the study. The increase was even higher, on average 314/µL, in patients with greater than 3 log HIV RNA mean suppression from baseline, according to the report.
Dr. Phillips and colleagues found that "[t]here is an initial phase, lasting 4-8 weeks, of rapid CD4 count increases followed by a long phase of more gradual rise." Cell counts continued to rise between weeks 64 and 72, "...suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed."
Based on these data, the authors recommend that "...the aim of therapy should be to achieve prolonged viral suppression of at least 3 log."
They speculate, "Given the magnitude of the increase we observed in the group with the most viral suppression, and the fact that the level was still rising at week 72, the possibility-given enough viral suppression over enough time-of ultimate full regeneration of CD4 cell numbers cannot yet be ruled out."
Even patients with baseline CD4 cell counts of less than 10/µL experienced increases of the same magnitude as patients with higher initial counts, so "...reversal appears possible even in patients with very advanced disease."
Ref: AIDS 1999;13:951-956. Source: Reuters Health
Data from the National Hospital Discharge Survey show declines in hospital use for patients with human immunodeficiency virus (HIV) from 1995 to 1997. These trends in inpatient care are consistent with declines reported in mortality and morbidity for HIV. The age-adjusted death rate per 100,000 population for HIV dropped from 15.6 in 1995 to 5.9 in 1997. This unprecedented decline has been attributed to use of intensive antiretroviral therapies. These drugs also appear to have had a major impact on the need for hospital care for the HIV.
HIV patients had 71,000 fewer hospitalisations in 1997 than in 1995. Their average length of stay in the hospital was 1.2 days shorter in 1997. This resulted in 878,000 fewer days of hospital care for HIV patients. Both the number and rate of hospitalisations fell by approximately 30% during this period, and the number and rate of days of care declined by almost 40%.
More than 70% of the hospitalisations for HIV in both 1995 and 1997 were for patients 25-44 years old. Within this age group, hospitalisations for HIV patients who were 25-34 years old decreased by a third. The changes in the number of days these HIV patients spent in the hospital were even more dramatic, including drops of 50% for those 30-34 year old and of more than 40% for those 25-29 and 40-44 year olds.
The National Hospital Discharge Survey, a survey of patients discharged from a sample of the nation's non-federal short-stay hospitals, has been conducted annually by NCHS since 1965 to profile patterns and monitor change in hospital care in the United States. Additional data from the survey are presented in NCHS publications and available in public use electronic data sets available on the NCHS home page at:
Anal cytology screening provides "substantial" clinical benefits to HIV-positive homosexual and bisexual men, according to a multicentre team. And these benefits can be achieved "...at a cost comparable with other accepted clinical preventive interventions." HIV-positive homosexual and bisexual men are known to be at increased risk of human papillomavirus-related anal squamous intraepithelial lesions (ASIL) and anal squamous cell carcinoma (SCC). This led Dr. Sue J. Goldie of the Harvard School of Public Health and colleagues to investigate the clinical benefits and cost-effectiveness of anal cytology screening in this patient subgroup.
They performed a cost analysis for a hypothetical cohort of HIV-infected homosexual and bisexual men, comparing lifetime costs, life expectancy, and quality-adjusted life expectancy between screened and unscreened subjects. "Screening for ASIL increased quality-adjusted life expectancy at all stages of HIV disease," the researchers report in the May 19th issue of The Journal of the American Medical Association. When performed every 2 years, starting in early-stage HIV infection, anal Papanicolaou (Pap) screening "...resulted in a 2.7-month gain in quality-adjusted life expectancy for an incremental cost-effectiveness ratio of $13,000 per quality-adjusted life year saved."
Yearly Pap screening extended the clinical benefits "...at an incremental cost of $16,600 per quality-adjusted life year saved." Dr. Goldie's group also found that yearly Pap screening was preferable when screening was initiated later in the course of HIV infection. No substantial advantages were seen when Pap screening was performed every 6 months.
"Regardless of when screening was initiated, the cost-effectiveness of either a yearly or every-2-year screening schedule was comparable with other accepted preventive measures in clinical medicine," they conclude. Based on these findings, Dr. Goldie's team recommends that "...immediate consideration be given to identifying the real-world barriers associated with implementing such a screening policy."
Ref: JAMA 1999;281:1822-1829. Source: Reuters Health
Preliminary data suggest that highly active antiretroviral therapy (HAART) does not change the natural history of HPV-related anal dysplasia in HIV-infected patients, according to Dr. Joel Palefsky of the University of California at San Francisco. Speaking at the National Cancer Institute's Third Annual National AIDS Malignancy Conference, Dr. Palefsky said that in a small study he conducted in HIV-positive men, HAART had no real impact on progression or regression of anal squamous intraepithelial lesions (ASIL). Before the advent of HAART, many patients with ASIL did not progress to cancer because they usually died before the malignancy could develop. In studies of cervical cancer, HAART has begun to delay malignancy, and Dr. Palefsky and colleagues wanted to see if this were so for anal cancer. Dr. Palefsky studied 78 HIV-positive men before HAART was begun, and 6 months after. All had HPV infection and either no anal disease, or evidence of low-, medium-, or high- grade SIL. Subjects without disease did not progress. For those with low-grade lesions, there was some progression in the pre-HAART period, and less in the post-HAART period. The same was true of high-grade patients. But Dr. Palefsky found that the patients with a higher CD4 cell count at baseline tended to respond better. "The conclusion is that HAART isn't having a big impact one way or the other," he said. He noted that the data suggest the risk of anal cancer may continue to rise in the HAART era because patients tend to live longer. It takes about 3 decades after initial sexual contact for cervical cancer to develop, Dr. Palefsky said. "We need to continue to be very vigilant, particularly in individuals who are living longer with high grade lesions." Dr. Palefsky said he plans to continue the HAART/anal cancer study in more patients over a longer time period.
Source: Reuters Health
A report published in the June issue of the American Journal of Clinical Nutrition associates truncal enlargement in HIV patients with significant increases in visceral adipose tissue. Investigators used magnetic resonance imaging and dual-energy x-ray absorptiometry in their examinations. Visceral adiposity syndrome "...is associated with higher CD4 lymphocyte counts and lower plasma HIV viral burdens, and is not limited to those receiving protease inhibitor therapy," the researchers note. "Thus, the development of truncal adiposity, rather than being a direct effect of protease inhibitors, may be a response to the return toward health that these drugs promote." Furthermore, they added that visceral adiposity syndrome is not only related to protease inhibitor therapy.
Source: CDC HIV/STD/TB Prevention News Update
A report presented at the Third Annual National AIDS Malignancy Conference recommends the use of highly active antiretroviral therapy (HAART) along with chemotherapy, when treating HIV-related non-Hodgkin's lymphoma. Investigators studied HIV-positive patients receiving a low-dose chemotherapy regimen and a high-dose chemotherapy regimen. The combination of chemotherapy and HAART was well tolerated, few negative drug interactions were observed, and toxicity's were similar to those in patients without HIV.
Source: CDC HIV/STD/TB Prevention News Update
Initial data suggests that Interleukin 12 (IL-12) proves effective in fighting AIDS-related Kaposi's sarcoma. Subjects self-administered escalating doses of IL-12 twice a week, utilising a subcutaneous delivery system. The investigators found that seven of nine evaluable patients achieved a 50 percent drop in number or size of lesions and no evidence of progression. The subjects responded within 16 weeks, on average. The researchers, who presented their findings last week at the Third National AIDS Malignancy Conference, said the data was encouraging, because IL-12 was very well tolerated, unlike IL-2.
Source: CDC HIV/STD/TB Prevention News Update
A study published in the June issue of the Journal of Immunology suggests that some human major histocompatibility complex (HLA) proteins may slow or hasten the speed at which HIV-1 progresses. The study observed 200 slow progressers and 75 fast progressors. Quantitative analysis showed that nonprogression was related to HLA class I genes B14 and C8 and that rapid progression was associated with HLA class I genes A29 and B22. The authors of the study, from the Universite Pierre et Marie Curie in Paris, emphasise that no HLA alleles provide very long-term protection from HIV progression.
Source: CDC HIV/STD/TB Prevention News Update
The presence of a high viral load, together with positive viral isolation in culture, are associated with increased risk of heterosexual transmission of HIV, according to Spanish investigators.
Dr. Jose Alcami of Hospital 12 de Octubre in Madrid and associates examined virologic parameters that may influence the risk of heterosexual transmission. Although heterosexual transmission is the primary mode of HIV infection world-wide, the associated risk factors are still poorly understood, they explain in the June 1st issue of the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology.
Dr. Alcami's group evaluated 38 discordant heterosexual couples, who despite intensive counselling and behavioural intervention, continued to have unprotected sex. Both the index cases (HIV-infected) and the partners (HIV-negative) were evaluated every 6 months.
HIV transmission occurred in 10 of the 38 couples. The investigators observed significant differences in mean viral loads between the transmitting couples and the nontransmitting couples. The mean viral load of the transmitters was 21,139 HIV RNA copies/mL, whereas the mean viral load of the nontransmitters was 5484 HIV RNA copies/mL. In addition, viral isolation was possible for 90% of the transmitters compared with 44% of the nontransmitters. However, Dr. Alcami's group found no differences between the 2 groups in "...clinical characteristics, exposure time, sexual practices, CD4 counts, or polymorphism in CCR5."
Based on the findings, they conclude that "...viral parameters of the index cases, such as viral load and a positive isolation in culture, must be considered as risk factors for the heterosexual transmission of HIV." Ref: J Acquir Immune Defic Syndr Hum Retrovirol 1999;21:120-125.
Source: Reuters Health
Researchers from Australia's LaTrobe University say that heterosexual men with HIV may be under-treated. A survey of 143 HIV-infected heterosexual men suggests that this group is less likely to have regular viral load tests and is less likely to use new therapies to combat the disease. Investigators hope that new information on this group will prompt funding bodies and services to address the problem.
Ref: Australian Broadcasting Corp. News Online (24/05/99) Source: CDC HIV/STD/TB Prevention News Update
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...and finally
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An advisory panel to the Food and Drug Administration has recommended that American travellers who stayed in Great Britain for over six months between 1980 and 1996 should be barred from donating blood. The FDA panel is concerned about a possible risk that a human brain disease similar to bovine spongiform encephalopathy, or mad-cow disease, could be able to spread via blood; this has never happened in humans, but some scientists are worried about the theoretical risk. The concern arose from reports by British researchers that some people seemed to be exhibiting symptoms of brain disease after eating meat contaminated with bovine spongiform encephalopathy. An American Red Cross study found that 23 percent of U.S. blood donors travelled to Great Britain between 1980 and 1996.
Ref: Wall Street Journal (www.wsj.com) (03/06/99) P. B16 Source: CDC HIV/STD/TB Prevention News Update
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HIV and Pregnancy Meeting
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Dr Beckerman works with women with HIV - pre-conception, during pregnancy, delivery and for their babies' first year. Her program places great emphasis on the mothers' own health and, using HAART throughout pregnancy has rates of mother-to-child transmission of almost zero. Women are provided with the most up-to-date treatment information available, in a form that they describe as 'Educational, Supportive, Non-directive'. She explains, 'We don't push clients, we don't tell them what is right, but we do ensure that they are very well informed before they make any decisions'.
The AIDS Treatment Project (ATP) will be hosting these meetings and will also be publishing an interview with Dr Beckerman in the summer issue (#6) of their newsletter Positive Treatment News (PTN). Both meetings are by invitation only, any enquiries please contact ATP's Events and Projects Co-ordinator Kimberly Gray on 0171 407 0777.
Contacts:
Anne Parker (0171 833 4828), Body and Soul, The Royal Homeopathic Hospital, 60 Great Ormond Street, London WC1N 3HR
Kimberly Gray (0171 407 0777), AIDS Treatment Project, St Stephen's House, 115-29 Southwark Bridge Road, London SE1 OAX