Medical Consultant
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ANTIRETROVIRALS
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Gilead Sciences, Inc. has announced the extension of its U.S. expanded access program for the investigational anti-HIV drug adefovir dipivoxil (Preveon®) to Europe, Canada and Australia. Designed for people with advanced HIV infection who have limited treatment options, the program recently started enrolling patients in France and will begin enrolment in additional European countries, Canada and Australia as regulatory approvals are obtained. Adefovir dipivoxil is an investigational, once-daily, reverse transcriptase inhibitor being studied in combination with other antiretroviral agents in late-stage Phase III clinical trials for the treatment of HIV infection. It is the first anti-HIV nucleoTIDE analogue to reach this stage of development
The program will make adefovir dipivoxil available free of charge to HIV-positive patients at least 13 years of age who have failed treatment with at least two nucleoside analogue reverse transcriptase inhibitors and one protease inhibitor, regardless of their HIV RNA plasma level or CD4 cell count. Patients will receive a once daily dose of adefovir dipivoxil 60 mg and the nutritional supplement L-carnitine. In addition to adefovir dipivoxil, Gilead advises physicians caring for patients in the expanded access program to add to their patients' regimens at least one new antiretroviral agent that has not been previously administered.
Clinical Studies
In addition to the ongoing dose comparison trial (Study 417) to evaluate the relative safety and efficacy of the 60 mg and 120 mg doses of adefovir dipivoxil and the trial to evaluate use of the compound in treatment-naive patients (Study 411), Gilead has also initiated several new confirmatory studies of the compound in the United States, Europe, Canada and Australia. These trials are designed to further characterise the long-term efficacy and safety of adefovir dipivoxil 60 mg, explore emerging HIV treatment strategies and satisfy traditional regulatory guidelines for drug approval.
During clinical testing, the most common side effects reported with adefovir dipivoxil for HIV have been dose-related gastrointestinal effects, including nausea and loss of appetite. Nephrotoxicity, including changes in serum creatinine and phosphate, is the most important drug-related toxicity. These changes in renal function are generally gradual in onset, asymptomatic, detectable by routine laboratory monitoring and resolvable upon dose reduction or withdrawal. Elevations in liver transaminases have been observed in some patients.
Physician Registration
For specific information about the expanded access program in Europe and Australia, physicians may call the Quintiles European office directly at 33-3-88-77-45-98. Information about clinical trial locations also may be found by using the Clinical Trial Locator on the Gilead Web site at http:// www.gilead.com.
Source: Gilead Sciences Press Release (06/05/99)
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Adefovir appears to show increased activity (approx. 1 log as monotherapy) against HIV carrying the M184V (3TC associated) mutation. Standard activity (approx. 0.5 log) with M184V and zidovudine associated mutations or wild type. Adefovir also shows some activity against hepatitis B virus and CMV. Maintenance of the M184V mutation to enhance response to adefovir would argue for continuation of 3TC in the adefovir containing regimen. As this mutation is thought to increase fidelity during viral replication and may reduce biological fitness continued 3TC might also have additional benefits. Adefovir should be considered when attempting to construct a new regimen but careful monitoring for proteinuria and phosphates is required for early detection of proximal renal tubular dysfunction (the principal adefovir related toxicity). Using a 60 mg dose this is rarely observed before 6 months of therapy.
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Pfizer pharmaceuticals on April 21st released data from two interaction studies between their impotence drug sildenafil (Viagra®) and ritonavir, and sildenafil and saquinavir. It had been speculated that caution should be observed in the concomitant use of these drugs due to the shared metabolic pathways involved (predominantly CYP3A4). Amongst the currently available HIV protease inhibitors ritonavir is the most potent inhibitor and saquinavir the most moderate inhibitor of CYP3A4.
The pharmacokinetics of both ritonavir and saquinavir were unaffected by sildenafil co-administration. However, the pharmacokinetics of sildenafil was affected substantially by administration with the protease inhibitors.
The co-administration of saquinavir (Fortovase®) at steady state (1200 mg tid) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics.
Co-administration of the protease inhibitor ritonavir (Norvir®), at steady state (500 mg bid) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1,000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. Sildenafil had no effect on ritonavir pharmacokinetics.
These data led the European Medicines Evaluation Agency to issue a public statement in advance of package leaflet changes for sildenafil stating:
"Having reviewed these results it was concluded that co-administration of sildenafil with ritonavir is not advised. However, if sildenafil must be prescribed for a patient on ritonavir, the maximum dosage of sildenafil should not exceed 25 mg within 48 hours."
"For patients receiving concomitant treatment with potent CYP 3A4 inhibitors such as saquinavir, other HIV protease inhibitors, erythromycin, ketoconazole, and itraconazole, attention of prescribers is drawn to the current recommendation in the SPC (summary of product characteristics) that a starting dose of 25 mg of sildenafil should be considered."
"Patients currently being co-prescribed sildenafil and HIV protease inhibitors should contact their physician to receive further information and advice about their ongoing treatment".
Amyl nitrite (Poppers) and sildenafil
Sildenafil must not be combined with nitrite inhalants ("poppers") or any form of nitrates, because the combination may result in dangerously low blood pressure, which could be fatal.
Ref: EMEA statement (CPMP/1148/99)
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These data are essential to guide physicians and patients in the correct usage of these drugs when co-administered. If we fully understand the relative changes in plasma levels of sildenafil adjustments to dosage can easily be made and are the norm for therapeutic settings outside of HIV. The psychological and consequent physical effects of impotence are profound and represent a real cause for morbidity in certain patient groups. The decision to use such drugs as sildenafil should not be determined by views that its interactions with PI's are "adverse", this phenomena can be well defined, dosage adjustments of sildenafil can be made and the decision to use such drugs should remain in the control of those directly caring for patients. It should be emphasised that patients should not miss doses of ritonavir to take viagra - they should discuss dose modification with their doctor (perhaps starting with half a 25 mg tablet of viagra) or explore other forms of management for erectile dysfunction.
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S. Palmer and colleagues of Stanford University Medical Center, have reported the results of in vitro activity of 7 new reverse transcriptase inhibitors and 7 new protease inhibitors against 5 strains of drug-resistant HIV variants. Most of the HIV strains were resistant to the new compounds, and most of the resistance mutations were different than those that were selected with in vitro studies. Experimental protease inhibitors that showed high levels of cross-resistance were amprenavir, BMS 232632, DG-35, DG-43 and palinavir. Varying degrees of decreased susceptibility were noted with F-ddA, abacavir, adefovir, PMPA and PFA. The only new protease inhibitor tested that proved active against all isolates was the cyclic urea amide, SD 146. However efforts to develop a soluble form of this compound have so far failed and it has been unable to enter clinical development.
The drug resistant viral strains used were selected on the basis of the prevalence of these mutants in patient samples from local HIV clinics (Stanford, California). The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 endpoint.
The authors urged that pre-clinical development of new drugs should include testing of activity against currently circulating strains of HIV that are highly drug-resistant to determine potential use for salvage regimens.
Ref: Palmer S, Shafer RW, Merigan TC. Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development. AIDS 1999, 13:661-667.
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The implications of this article are profound and highlight the fact that viruses mutating during current antiretroviral treatment are already resistant to the next generation of drugs in the pipeline. This is unsurprising given that many new drugs are variations on a theme e.g. peptidomimetic PI's, nucleoside analogues (ddA as active forn of ddI) etc. Thus choice may expand for initial therapy but salvage remains a struggle. Even initial therapy will eventually be affected as the transmission of drug resistant HIV becomes more widespread. The lack of significant new agents emphasises the need to optimise available therapies to ensure durability through supporting adherence, determining pharmacological issues associated with failure (through therapeutic drug monitoring) and of course reviewing the evolution of resistance.
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The British HIV Association has published a discussion draft of its 1999 treatment guidelines. The full document can be downloaded from the joint British HIV Association / National AIDS Manual website at http://www.aidsmap.com
Referenced comments on the guidelines, which will be revised after the one month discussion period, can also be submitted via the site.
Key points include:
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It is important that everybody has input into these guidelines not just to ensure adequate patient care but because they are inevitably used to justify funding decisions.
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An updated version (May 1999) of the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents has been posted to the AIDS Treatment Information Service (ATIS) Web site, www.hivatis.org. This is in portable document format (pdf). The full document formatted for your web browser is also available courtesy of Medscape at:
http://hiv.medscape.com/govmt/DHHS/guidelines/HIV/HIV-01.html
The update includes information on the use of abacavir (a nucleoside reverse transcriptase inhibitor) in combination with other approved therapies, the addition of hydroxyurea to certain antiretroviral regimens (provided as supplemental information), and a new comprehensive listing of drug interactions between antiretrovirals and other drugs (Table XI).
The Guidelines were developed by the Panel on Clinical Practices for the Treatment of HIV Infection, a joint effort of the Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The Guidelines were constructed as a "living document" and are updated frequently by the Panel.
The Panel also considered recently published data suggesting that HIV-infected women experience more rapid disease progression compared with men who have the same level of virus in their bloodstream. These data were obtained in studies of women who were injecting drug users, and the results have not been consistently observed in other studies. The Panel therefore did not recommend that women begin antiretroviral therapy earlier than men, but will continue to closely follow developments in this field.
A report in the May issue of Clinical Infectious Diseases suggests that discontinuing lamivudine in persons co-infected with HIV and hepatitis B may cause serious flares of hepatitis B. The drug is active against both viruses; however, a mutation at the YMDD locus that both viruses' share plays a role in lamivudine resistance, the authors note. The retrospective study identified five patients who had serious flare-ups after discontinuing lamivudine, including three who developed signs of resistance mutations to the drug.
Two patients experienced a resurgence of hepatitis B after they were switched from an antiretroviral regimen that contained lamivudine to highly active antiretroviral therapy (HAART) that did not include lamivudine. In 1 case, the patient's condition improved after lamivudine was started again. The other patient developed fulminant hepatitis and died. The 3 other cases involved patients who experienced a worsening of hepatitis B infection while on lamivudine. According to Dr. Bessesen's team of the Veterans Affairs Medical Center in Denver, Colorado, this phenomenon indicates the emergence of resistance mutations.
The investigators point out that HIV infection has been associated with a diminished inflammatory response to HBV. However, immune reconstitution appears to "...shift the spectrum of disease toward an enhanced inflammatory response to hepatitis B followed by decreased viraemia and seroconversion."
Ref: Clin Infect Dis 1999;28:1032-1035.
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This report illustrates the complexity of both HIV therapy and the pathogenesis of the disease itself. 3TC being active against HIV and HBV underlines that we should not be treating co-infected patients with what is essentially HBV monotherapy. Inclusion of famciclovir, adefovir and/or interferon should be considered as part of a regimen for this group of patients. The issue becomes more complex when the immune reconstitution generated by efficient antiretroviral therapy is considered. Disease processes such as HBV involving immune response in their pathogenesis may be reactivated during antiretroviral therapy. Indeed the reactivation of HBV was described as early as 1995 by Cooper as an observation during ritonavir monotherapy studies.
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Abstract
Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.
Ref: Zhang ZQ, Schuler T, Cavert W et al. Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5169-5172
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Clearly the reversal of pathological changes in the FDC network after longer term therapy is good news, especially so in patients starting antiretroviral therapy with advanced disease. Balanced against the data from other immunologists suggesting certain elements of acquired immunity may be lost for ever in advanced disease this data is further support for views suggesting delayed therapy may still be equally efficacious in the longer term. It should be noted that these data on the FDC network were obtained from subjects receiving protease inhibitor based combination therapy and may be a class effect not applicable to NNRTI or triple nucleoside analogue therapy.
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OPPORTUNISTIC EVENTS
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Researchers for the Swiss HIV Cohort Study investigated the feasibility of discontinuing primary prophylaxis against Pneumocystis carinii pneumonia in HIV-infected patients who are treated successfully with combination antiretroviral therapy. Eligible participants included those who CD4 counts had risen to at least 200 cells per cubic millimetre and 14 percent of total lymphocytes while taking combination antiretroviral therapy. Prophylaxis was discontinued at study entry. Over a median follow-up of 11.3 months, prophylaxis was resumed in nine of the 262 patients studied, and two died. No cases of PCP or toxoplasmic encephalitis were diagnosed. Investigators concluded that stopping primary prophylaxis was safe in HIV-patients who are receiving antiretroviral therapy and who have sustained CD4 counts of at least 200 cells per cubic meter and to a minimum of 14 percent of total lymphocytes.
Ref: Furrer, Hansjakob; Egger, Matthias; Opravil, Milos; et al. New England Journal of Medicine (29/04/99) Vol. 340, No. 17, P. 1301. Source: CDC HIV/STD/TB Prevention News Update
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These data follow those of the Eurosida study reported in ATP's Doctor Fax Issue 67. In an accompanying editorial to the NEJM paper Dr. Henry Masur of the National Institutes of Health, and Dr. Jonathan Kaplan, of the Centers for Disease Control and Prevention, discuss new research on discontinuing Pneumocystis carinii pneumonia prophylaxis in HIV-infected patients. The authors found that considering the representative nature of the study cohort, and the demonstrated potential of antiretroviral regimens in reconstituting immune system response, discontinuation of PCP prophylaxis may be beneficial for a number of reasons. Kaplan and Masur believe that simplifying the HIV regimen, and the psychological benefits are worthwhile. "On the basis of available data, it would seem reasonable to consider discontinuing primary prophylaxis against P. carinii pneumonia if the CD4 count exceeds 200 cells per cubic millimetre for a sustained period," they note, although it is not yet clear how the sustained period should be defined. They also note that discontinuing prophylaxis in patients with persistently high viral loads or those who do not have sustained responses to antiretroviral therapy may not be advisable.
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Limited, open label, controlled clinical studies evaluating the safety and efficacy of fomivirsen have been conducted in patients with newly diagnosed CMV retinitis and in patients who have failed previous therapies. Based on the assessment of fundus photographs, the median time to CMV retinitis progression was approximately 80 days in patients receiving a dose of 330 µg. Many of these patients were also receiving protease inhibitor treatment. In the subgroup of newly diagnosed patients who received delayed treatment, most had CMV retinitis progression within two weeks. Head to head comparisons with other medications available to treat CMV retinitis have not been completed.
Source: Ciba Vision press release.
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Fomivirsen is based on antisense technology, a type of gene therapy. The drug is an oligonucleotide, a short chain of nucleotides (the building blocks of genetic material). The antisense compound works by interfering with the decoding of CMV's genetic material. In order to produce new proteins, the part of the virus' DNA that encodes a specific protein (a sense sequence) is copied to messenger RNA. Fomivirsen is a complementary (antisense) sequence that binds to the messenger RNA sequence and blocks CMV's ability to make the proteins it needs in order to replicate.
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Poppers: Large cancer increase and immune suppression seen in animal studies
A new study found that mice injected with cancer cells were more than three times as likely to develop tumours if they inhaled isobutyl nitrite--"poppers"--and that when tumours did develop, they grew four times as rapidly in the inhalant- treated animals. 75% of the mice receiving nitrite developed the tumours in this test, vs. 21% of the control mice (which received the same cancer cells but breathed only air instead). The amount of inhalant used--900 parts per million for 45 minutes a day--was selected to approximate social use of the drug.
Other laboratory tests found that isobutyl nitrite did not increase growth of the tumour cells; instead it suppressed certain immune functions, including cytotoxic T lymphocyte (CTL) activity, and the killing of tumour cells by macrophages--which was reduced 86% by 5 days exposure to the inhalation. Previously published work by the same team (2) found that immunity in the mice recovered within 14 days of stopping the inhalant. (The current paper suggested that permanent damage might still be done if immune suppression allowed cancer, KS, or HIV itself, to become established.)
This is the first study showing directly that nitrite inhalant can promote tumour growth. Previously, epidemiological studies had found that use of poppers is associated with KS, and also is an independent risk factor for infection with HIV (suggesting that poppers may increase the risk that exposure to HIV will lead to infection). KS is believed to be caused by a different virus, HHV-8, that presents little risk unless the immune system is suppressed by other factors. (The tumour cells used in this research were not KS, but they were a well-known cell line used in animal tests to measure immune suppression.)
Comment
Malignancies are a major and increasing problem in AIDS, and it will be important to find out if use of poppers is contributing to their higher incidence. One way to research this question would be to ask whether or not patients with lymphoma or other malignancies are more likely than others to have used these drugs.
Ref: Soderberg LSF. Increased tumour growth in mice exposed to inhaled isobutyl nitrite. TOXICOLOGY LETTERS, 1999; volume 104, pages 35-41. Source: AIDS Treatment News, Issue 317, April 16, 1999. Subscription and Editorial Office, P.O. Box 411256, San Francisco, CA 94141.
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PATHOGENESIS
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Latent HIV-1 infection may persist in resting CD4+ T cells for up to 60 years, even in patients on combination antiretroviral therapy with undetectable plasma virus, according to a report in the May issue of Nature Medicine. In 1997, latent HIV infection was found to persist in the resting CD4+ T cells of patients on combination therapy, even when no free virus is detectable in plasma, at that time it was not clear how long these cells would survive.
To further investigate this, Dr. Siliciano and colleagues at Johns Hopkins University in Baltimore, Maryland, and elsewhere evaluated the decay rate of the latent viral reservoir in 34 HIV-1-infected adults. All of the subjects, who had responded well to highly active antiretroviral therapy, were selected on the basis of strict adherence to their treatment regimen and persistent, undetectable (below 200 copies/mL) viral load. "Through direct longitudinal analysis of the decay rate of the latent reservoir, we have demonstrated that the reservoir is very stable, with a half-life of more than 43 months in the average patient on current 'standard of care' therapy," Dr. Siliciano's group reports. "Even with conservative estimates of the total body number of latently infected cells, an average of at least 60.8 years of treatment will be required to eradicate this compartment in most patients."
A few of the patients in the group were in the acute stages of infection, "...in the window period where they had a lot of virus in the blood, but had not yet made an immune response," Dr. Siliciano continued. "And even in those patients, this latent pool is generated and then appears to decay very, very slowly." The clinical implications of this research are that "...you're not going to be able to just wait it out. These cells are not going to decay in a clinically meaningful time-frame." Therefore, something else must be done, he said, such as strengthening the immune response so it can handle the low amount of virus or developing some novel way to directly target these cells.
"Alternatively, patients can simply remain on therapy." Dr. Siliciano stressed that "...there's nothing in our research to suggest that patients can't continue to do fine as long as they adhere to the regimen. But the notion that you can just treat for a long time and expect eradication, I think is now no longer reasonable given this new information." It is also "...possible that better regimens will be developed that suppress the virus even better than the current regimens." However, he points out that this "...may or may not help. It depends on whether this reservoir is being maintained by a low level of ongoing replication. If it is, then perhaps a better regimen will suppress that replication and give you a faster decay rate. But we're not sure that that's the case. It may just be that it's maintained by other mechanisms that don't involve ongoing viral replication."
Ref: Nat Med 1999;5:512-517. Source: Deborah Mitchell, Reuters Health.
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60.8 years of totally suppressive therapy for eradication - a daunting prospect indeed and clearly not an option with existing therapies. A powerful incentive not to commit to therapy when it may not yet be needed. However, if therapies increase in potency as well as tolerability improved virologic responses may require cellular DNA assays to monitor therapy and replication rates may be so slow that there is little viral evolution and therefore little resistance. Greater immune reconstitution may also allow host cellular immune responses to target latent infected cell populations. Approaches to stimulating HIV-specific CTL are currently under investigation (such as IL-2, IL-12, GMCSF, remune and "autovaccination" strategies).
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Abstract
Human immunodeficiency virus type 1 (HIV-1) infection is dependent on susceptible host cells that express both CD4 and chemokine co-receptors. The co-receptor CCR5 is associated with primary infection by macrophage-tropic virus isolates, whereas CXCR4 is commonly associated with T cell and dual-tropic viruses. Once infected, lymphocytes and macrophages may replicate HIV-1 or harbour latent virus, depending on environmental factors and cellular activation. Immune activation is often associated with viraemia, which is consistent with enhanced infection and viral replication in activated cells harbouring virus. In this regard, opportunistic infections activate the immune system with the detrimental sequelae of enhanced viral replication and viraemia. Under these conditions, viral expansion extends beyond T cells to tissue macrophages, many of which are co-infected with opportunistic pathogens. The opportunistic infections promote macrophage susceptibility to HIV-1 through cytokine modulation and altered chemokine co-receptors, potential targets for intervention.
Ref: Sharon M. Wahl, Teresa Greenwell-Wild, Gang Peng, Hollie Hale-Donze, and Jan M. Orenstein. The Journal of Infectious Diseases 1999;179:S457-S460.
Australian researchers, studying a small group of individuals who have been infected with HIV for years without any AIDS symptoms, recently ended their hope of developing a vaccine from the naturally weakened live virus strain. The patients, who contracted HIV via transfusions from one blood donor, have lived with HIV for up to 17 years. However, the donor was diagnosed in February with an AIDS-related infection of the brain and spinal cord, and two patients have weakened immune systems, although they have not become sick. The strain of HIV was weakened by a natural deletion of nef. The researchers will continue to study the three infected individuals who are still healthy.
Source: CDC HIV/STD/TB Prevention News Update
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This is disappointing but as least suggests that nef may be a reasonable target for therapy if deletion so dramatically delays disease progression. |
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IMMUNOTHERAPY
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Adjuvant treatment with Granulocyte-macrophage colony-stimulating factor (GMCSF, sargramostim, Leukine®) may help HIV-infected patients on combination antiretroviral regimens maintain viral suppression and extends the efficacy of these regimens, according to a press release from Immunex Corporation.
Phase III trial results for GMCSF were presented at the Eighth Canadian Conference on AIDS/HIV Research. The 309-patient, Phase III, double-blind, randomised, placebo-control trial evaluated the impact of GMCSF on the incidence of opportunistic infections, the rate of survival and changes in viral load, CD4+ T cell counts and absolute neutrophil counts. Changes in therapeutic regimens were also monitored in this study. All patients in the trial were diagnosed with late-stage AIDS (patients entering the study had CD4+ T cell counts of less than 50, or less than 100 with a prior AIDS-defining opportunistic infection). Patients were stratified into two groups based on baseline viral loads of below or above 30,000 copies/mL. Patients received either GMCSF or a placebo three times per week for six months as an adjunct to standard antiretroviral therapy. Physicians were permitted to change antiretroviral therapy to manage the patient's viral load. Forty-five percent of patients participated in an optional, blinded study extension up to 20 months of treatment.
Among 115 patients with viral loads less than 30,000 copies/mL, 81 percent of the GMCSF patients were able to remain on the same antiretroviral regimen and maintain baseline level of viral suppression throughout the duration of the study as compared to 62 percent of the patients receiving placebo. In the six-month study, patients with undetectable virus (less than 400 copies/mL) who received GMCSF were more likely to maintain undetectable viral loads than patients receiving placebo. In 57 patients with undetectable virus at study entry, 83 percent of GMCSF patients continued to maintain undetectable viral load at 24 weeks as compared to 54 percent of placebo patients. GMCSF was generally well tolerated. The Phase III study also found that patients in both cohorts treated with GMCSF nearly doubled mean CD4+ T cell counts from 51 at the start of the study to 94 at six months while patients in the placebo group had an increase in cell counts from 50 to 71. Also, at six months, GMCSF increased mean absolute neutrophil counts by 884 as compared to 266 among patients receiving placebo. Side effects occurring more frequently with GMCSF than placebo included injection site reactions and weight loss. Injection site reactions were mostly mild and did not require treatment; weight decreases were typically mild.
Source: Immunex Corporation press release
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GMCSF may be a useful addition to regimens for patients with advanced disease, especially if also experiencing neutropaenia. Improved survival has been previously reported with GCSF. Improved macrophage function, surveillance of OI's and reservoir "flushing" may all play a part in mechanism of action. |
The development of new strategies to enhance the immune system of HIV-infected patients, even in those with early stage disease, may be more important than previously thought, according to the results of a study published in the May issue of Nature Medicine. The investigators found that gag-specific CD4+ memory T cells are detectable in most individuals with active, progressive HIV infection, whereas the levels of such cells decline in patients who maintain continuous viral suppression with antiretroviral therapy.
Results of previous studies suggest that in most individuals HIV-1-specific CD4+ T-cells are eliminated in the early stages of HIV-1 infection, and therefore do not contribute to host defence against the virus, Dr. Louis J. Picker of the University of Texas Southwestern Medical Center in Dallas and colleagues explain. However, this is inconsistent with data indicating that CD4+ T cells are essential to the development and maintenance of CD8+ T-cell effector responses, which are observed in patients with advanced HIV-1 disease.
To better understand these relationships, Dr. Picker's group used a multiparameter flow cytometric assay to detect antigen-specific memory CD4+ T cells in patients with nonprogressive HIV infection, untreated active HIV infection, and HIV suppression as a result of antiretroviral therapy. They found that "...significant frequencies of gag-specific, T-helper CD4+ memory T cells are detectable in most subjects with active/progressive HIV-1 infection." While the median frequency of these cells was "considerably higher" in nonprogressors (0.40%) than those with active disease (0.12%), they noted a "...substantial overlap between the two groups."
In contrast, patients on antiretroviral therapy with continuous HIV suppression exhibited a progressive decline in gag-specific CD4+ memory T cells. Median frequencies were "...0.08% in subjects treated for 4-24 weeks, and 0.03% in subjects treated for 47-122 weeks." Based on these findings, Dr. Picker's group concludes that "...immunologic participation in long-term HIV-1 control will probably require vaccination strategies."
Another clinical implication of this study somewhat counters the previous assumption that the only way to preserve CD4 cell function is to treat people during HIV seroconversion, Dr. Picker said. "Our data suggest that that's probably not true in most patients." However, new strategies to preserve the immune response in HIV-infected patients are needed, he continued, and the earlier the intervention the better. Whatever immune response patients do have should be preserved while patients are on highly active antiretroviral therapy (HAART). Therefore, Dr. Picker believes that immune preservation strategies, through vaccination or other approaches, should be conducted simultaneously with the control of viral load.
The study by Dr. Picker's team "...conclusively shows that there is indeed a significant loss of CD4+ helper memory [cells], that may lead to inefficient immunological control and successful escape of the virus from the reservoirs," Dr. Guy Gorochov of the Hopital Pitie-Salpetriere in Paris comments in a related article. However, it is still unclear "...whether HIV-specific CD4 memory is completely lost after effective anti-HIV treatment, or whether it merely falls below the detection-threshold of the assay." In any case, the findings highlight the importance of developing "...clinical protocols leading to stimulation of anti-HIV immunity or passive transfer of HIV-specific effectors in association with HAART."
Ref: Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, Picker LJ. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 1999;5:518-525. Ref: Guy Gorochov. Dangerous T-cell amnesia. Nat Med 1999;5:483-484 Source: Reuters Health.
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These data clearly underline that if host immune responses are to be incorporated into long term strategies they will need to be fostered. Viral suppression without eradication leads to a weakening of host response to HIV and increasing possibility of loss of control unless drug suppression is total. Indeed it has already been suggested that if the host immune system is "the 4th drug" then failure to antiretroviral therapy may be secondary to loss of specific anti-HIV immune control, resistance to antivirals being the final step in this failure pathway. |
Jeffrey T. Safrit, Ph.D. Yerkes Research Center & Emory University School of Medicine.
The debate about the pathogenic or protective role of CD8+ T cells in lentiviral infections may be leaning more and more toward one side of the argument. Understanding the true role of these cells in vivo is critical to both our understanding of HIV pathogenesis and for the design of vaccine candidates. To this end, clinical evidence has been accumulating for the past few years on the potential of the cellular immune response to control viral replication in HIV-1 infected individuals. Now, a recent report by Jšrn Schmitz et al. from the laboratories of Drs Keith Reimann and Norman Letvin has provided direct evidence for the positive role of CD8+ T cells in controlling virus in SIV-infected macaques (1).
These investigators successfully depleted CD8+ lymphocytes in rhesus macaques infected with SIV-mac251 and examined the effect of this depletion on viral load, Gag p27 antigenaemia, and SIV-Gag-specific CD8+ T cells during both the acute and chronic phases of infection, and on survival time.
Acute Infection
In an experimental setting that mimics primary HIV-1 infection in humans, rhesus macaques infected with SIVmac251 manifest extremely high viraemias that peak between days 7 and 10 post infection. This high viral load then rapidly declines over the next few days presumably due to the onset of the SIV-specific immune response. Others have argued, however, in favour of an exhaustion of appropriate target cells as a reason for this decline (2). In the present study, six acutely infected animals given a humanised anti-CD8 monoclonal antibody were completely depleted of CD8+ lymphocytes for a variable duration. In three of the animals, CD8+ cells were depleted for 17-21 days while the remaining three animals were depleted of CD8+ cells from 4 to as much as 9 weeks.
Despite the variability in time of depletion, the results were very consistent. In the CD8 depleted animals, viral RNA and Gag p27 antigenaemia remained higher for longer than in animals treated with a control antibody. In fact, in the animals that were depleted of CD8+ lymphocytes for >4 weeks, viral RNA and gag p27 antigen were never controlled and all three developed disease rapidly. These results are more consistent with the hypothesis that reduction of acute viraemia is due to the SIV-specific CD8+ T cell response than due to exhaustion of target cells.
Previous attempts at assessing the consequences of in vivo CD8+ cell depletion on the course of SIV infection have been hampered both by the variability of the viral loads and the incomplete depletions that were achieved (3, 4). In a study of protection provided by attenuated SIV strains, Stebbings et al. determined that CD8+ cells were not necessary for protection from subsequent wild type virus infection (3). In addition, Matano et al. depleted CD8+ cells prior to or during early SHIV infection (4). They found ensuing viral loads to be higher while CD4+ cells were lower than controls, suggesting a role for CD8+ cells in clearance of viraemia. However, the CD8+ cells depletions in both sets of experiments were partial and thus the results must be interpreted with caution. In addition, the number of macaques per experiment prevented any statistically significant results. Both of these hurdles were overcome in the study by Schmitz et al. (1). The use of a "humanised" monoclonal may have been the difference as the half-life and thus effectiveness of the antibody would likely be increased due to the reduction of any anti-monoclonal immune responses in the macaques. The previous studies used unmodified murine monoclonal antibodies.
Chronic Infection
Two recent studies have addressed the role of CD8+ lymphocytes in controlling virus during chronic SIV infection of macaques. Schmitz et al extended their findings in the acute infection model to examine the effects of CD8+ cell depletion in animals infected with SIVmac251 for greater than nine months (1). Jin et al. depleted CD8+ lymphocytes in seven macaques (six infected with SIVmac251 or 239 for 1 to 4 years and one uninfected control) (5). Both studies achieved transient depletions of CD8 cells lasting from 8-14 days. Interestingly, the humanised anti-CD8 monoclonal antibody appeared to be no more efficient than a murine anti-CD8 when used in the chronic infection setting. Nonetheless, both studies were able to show dramatic rises in viraemia during the window of depletion. As expected, when the CD8+ cells returned, viraemia fell back to the original chronic levels, consistent with the conclusion that CD8+ lymphocytes are responsible for controlling levels of virus.
A noted difference among the studies above was the effect of the depletion and increased viraemia on the macaque CD4+ lymphocytes. While Schmitz et al made no reference to changes in the CD4+ subset in either the acute or chronic infection experiments, the studies of both Jin et al. and Matano et al. noted declines in CD4+ lymphocytes coincident with the rise in viraemia. The CD4+ cell levels returned to pre-CD8 depletion levels as virus was again controlled by the CD8+ cells. The later results seem to be more in line with what would be expected during even a transient dramatic increase in viraemia. These results are also consistent with the typical pattern seen in acute HIV infection when the high viral loads result in declines in CD4 cells that usually return to baseline as virus is controlled (6).
Role of Antigen Specific CD8+ Lymphocytes
As CD8+ lymphocytes may be able to control virus by a number of specific and nonspecific mechanisms, it was reasonable to ask to what extent SIV-specific CD8+ cytotoxic T lymphocytes (CTL) might be involved in the control of virus in vivo . Schmitz et al followed SIV gag-specific CTL in Mamu A*01 animals during and after the depletions by flow cytometric staining with SIV peptide tetramers (p11c, C-M) (1). During acute infection, the appearance of tetramer positive CTL was delayed by CD8+ cell depletion but arose coincident with the control of viraemia in the Mamu A*01 animal where depletion lasted < 21 days. In contrast, in a Mamu A*01 animal that was depleted of CD8+ cells 28 days, tetramer positive CTL were never observed and virus was never controlled. Interestingly, when gag-specific CTL were followed during the chronic infection experiment, a significant boost of the pre-depletion levels of tetramer positive cells occurred that was coincident with the control of viraemia following the transient depletion.
Implications
These studies emphasise the potential relevance of virus-specific CD8+ lymphocytes in the context of prophylactic HIV vaccines. By their nature, induced CD8+ cells would serve as a second line of defence in situations where virus broke through antibody containment and was able to infect cells in the new host. The above results also suggest that therapeutic vaccines capable of boosting antigen-specific cellular responses may productively modulate viral replication in already infected individuals.
References
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NUTRITION
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Mortality risk in selenium-deficient HIV-positive children.
Abstract
Objective: To determine the independent contribution of specific nutritional factors on disease progression and survival in HIV-1-infected children.
Population: HIV-infected children (N = 24), who were perinatally exposed to the virus and symptomatic, were recruited between October and December of 1990 from the Jackson Memorial Pediatric Immunology Clinic, Miami, Florida, and observed for 5 years.
Methods: Immune status was measured by CD4 cell count; nutritional status was determined using serum albumin and plasma trace elements including iron, zinc, and selenium. Cox proportional hazards regression models were used to evaluate the relationship of these parameters to survival. Use of antiretroviral treatment was considered in the statistical model, and age at death was considered a parameter of disease progression.
Results: Over the course of the study, 12 children died of HIV-related causes. The final Cox multivariate analysis indicated that, of the variables evaluated, only CD4 cell count below 200 (risk ratio [RR] = 7.05; 95% confidence interval [CI], 1.87-26.5); p = .004], and low levels of plasma selenium (RR = 5.96; 95% CI, 1.32-26.81; p = .02) were significantly and independently related to mortality. Among the children who died, those with low selenium levels (< or =85 microg/L), died at a younger age, suggesting more rapid disease progression. Conclusions: In paediatric HIV-infection, low plasma level of selenium is an independent predictor of mortality, and appears to be associated with faster disease progression.
Although association is not causation the question should be asked if selenium administration makes a difference. Clearly merits a controlled study.
Kathryn Slayter of the Queen Elizabeth II Health Sciences Centre at Dalhousie University presented the results of a comparative study of sublingual vitamin B12 supplementation versus vitamin B12 injection. Low levels of vitamin B12 have been associated with anaemia in eight to twelve per cent of HIV-infected people. After screening patients at an HIV clinic for decreased vitamin B12 levels, six subjects were enrolled in the study. All subjects had vitamin B12 levels below 156 pmol/L. The subjects were randomised to receive supplementary vitamin B12 either sublingually (under the tongue) or by injection.
After one month of therapy, vitamin B12 levels had returned to normal in all subjects. As a result, the researchers conclude that sublingual vitamin B12 offers a safe and effective alternative to vitamin B12 injection, in addition to being less invasive and more convenient to take. In addition, sublingual vitamin B12 is associated with no risk of accidental exposure to HIV for health- care professionals administering vitamin B12 injections.
It should be noted that this study was extremely small and makes no specific reference to the effect of sublingual vitamin B12 on patients with varying degrees of immune suppression. These factors may affect the results seen in the general HIV population.Source: A report from the Eighth Canadian Conference on HIV/AIDS Research (Victoria, B.C.) (Abstract B202). From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Sublingual vitamin B12 as effective as injection