ISSUE 58 - Conference Report Special
|
Fourth International Congress on Drug Therapy in HIV Infection8-12 November 1998 - Glasgow, Scotland
|
Contents
- Antiviral Therapy 1998-1999: Smart HAART
- Rebuilding, Restoring, Reconstituting: Quality, not just Quantity, in the Immune System
- Children - Just Small Adults?
- Practical Issues: Resistance & Salvage, New Antivirals and Adherence
- Clinical Utility of Resistance Testing
- Different Treatment Strategy May Be Required For HIV+ Women Who Have Used Injection Drugs
- Treatment with IL-2 plus HAART markedly reduces HIV in immune system hiding places
- In-Vivo Anti-CD3-Induced HIV-1 Viraemia
- US FDA Approval of Abacavir Recommended
- Potent Suppression of HIV-1 Replication in Humans by T-20, a Peptide Inhibitor of Gp41-
Mediated Virus Entry
- Nevirapine - Caution for Chinese?
- UK Human Rights Act will allow challenges to treatment refusals
|
Fourth International Congress on Drug Therapy in HIV Infection 8-12 November 1998 - Glasgow, Scotland
|
The following selected reports are reproduced with permission from the comprehensive Next Day Summaries produced by Medscape Inc. (formerly Healthcare Communications Group), and published online at the Clinical Care options for HIV website:
All abstract numbers refer to Abstracts of the Fourth International Congress on Drug Therapy in HIV Infection, Glasgow, Scotland. AIDS 1998; 12 (Suppl 4):S1.
Antiviral Therapy 1998- 1999: Smart HAART
Author: Dr Graeme Moyle
Source: Clinical Care Options for HIV,
http://www.healthcg.com/hiv/
Rebuilding, Restoring, Reconstituting: Quality, not just Quantity, in the Immune System
Author: Dr Graeme Moyle
Source: Clinical Care Options for HIV,
http://www.healthcg.com/hiv/
Children - Just Small Adults?
Author: William G. Powderly, M.D.
Source: Clinical Care Options for HIV,
http://www.healthcg.com/hiv/
Practical Issues: Resistance & Salvage, New Antivirals and Adherence
Author: Graeme Moyle, M.D.
Source: Clinical Care Options for HIV,
http://www.healthcg.com/hiv/
Clinical Utility of Resistance Testing
Author: Ian G. Williams, F.R.C.P
Source: Clinical Care Options for HIV,
http://www.healthcg.com/hiv/
|
OTHER NEWS
|
Different Treatment Strategy May Be Required For HIV+ Women Who Have Used Injection Drugs
Findings from a decade-long study of HIV- 1-infected injection drug users indicate that HIV-1-positive women who have used injection drugs may need a different schedule for anti- AIDS therapy from current practice.
The research, published in the November 7 issue of The Lancet, show that, among study subjects who developed AIDS, levels of HIV were significantly lower in the women than in the men. This suggests that rates of disease progression are more rapid in HIV-infected women who have used injection drugs than do men with the same viral load. For example, according to three different methods of assessment, the women in this study who progressed to AIDS had viral loads measuring 38% to 65% of those in the men.
The men and women participating in the study developed AIDS equally quickly after infection, indicating that women who use injection drugs develop the disease with as little as half the viral load of men. In addition, at viral loads that equal mens', the women had 1.6 times greater risk of progressing to AIDS than are men.
"These findings could be an important first step in understanding the course of HIV/AIDS in each gender," said Dr. Alan I. Leshner, Director of the National Institute on Drug Abuse (NIDA), National Institutes of Health, which funded the study. "Continued research needs to answer whether this HIV progression holds for a non drug-using population as well. Further, it can be concluded that if a given viral load measurement differs in clinical significance in drug-injecting women, treatment strategies using these measurements may have to be optimised separately from those of men."
Led by Dr. Homayoon Farzadegan, a team of researchers at Johns Hopkins School of Hygiene and Public Health studied specimens from 650 HIV-1-infected, injection drug users participating in a continuous study at a Baltimore clinic. HIV-1 load was assessed during an initial (baseline) visit, and again on follow-up visits 3 years later. The study was designed to analyse the relationship between gender using three different methods of measuring HIV-1 viral load. Results demonstrated significantly lower median viral load measurements in women by all three methods.
"These results were surprising," noted Dr. David Vlahov of the Hopkins research team. "We expected lower viral loads to be associated with slower progression of the disease, and this was not the case."
Explanation for the lower viral load counts in women in the study remains elusive, with researchers considering several alternatives: different HIV-1 dynamics in men and women, and/or gender-linked behavioural differences that might influence viral load, and hormonal differences.
Source: NIH NEWS Ref: Farzadegan, Homayoon; Hoover, Donald R.; Astemborski, Jacqueline; et al. Lancet (07/11/98) Vol. 352, No. 9139, P. 1510
Treatment with IL-2 plus HAART markedly reduces HIV in immune system hiding places
Individuals treated with interleukin-2 (IL-2) plus highly active antiretroviral therapy (HAART) have significantly fewer resting CD4+ T cells in their bloodstream which harbour HIV than patients receiving HAART alone, according to a study of 26 patients conducted at the National Institute of Allergy and Infectious Diseases (NIAID). Resting CD4+ T cells are among the "safe havens" where HIV may persist for years - sewn into the cells' genes - despite aggressive three-drug antiretroviral therapy.
In resting CD4+ T cells taken from the bloodstream ("peripheral blood") of a small number of study patients receiving IL-2 plus HAART, the researchers have been unable to find HIV capable of replicating, even when they have looked for the virus in millions of cells with sensitive laboratory procedures.
Anthony S. Fauci, M.D., NIAID director and chief of the NIAID Laboratory of Immunoregulation (LIR), plans to present these new findings at the 36th Annual Meeting of the Infectious Diseases Society of America in Denver, Colo., on Sunday, November 15 at 8:30 a.m. Mountain Time. The lead LIR scientist on the new studies is Tae-Wook Chun, Ph.D., who, with Dr. Fauci and other colleagues, has published several seminal papers on latent reservoirs of HIV.
The NIAID team studied two different groups of HIV-infected patients, 12 receiving HAART (generally a combination of at least three antiretroviral drugs including a protease inhibitor) and 14 receiving HAART plus IL-2, administered either intravenously or subcutaneously. IL-2 is a regulatory protein of the immune system produced in the body by T cells. IL-2 has potent effects on the proliferation, differentiation and activity of a number of immune system cells, notably T cells. The 14 patients on HAART plus IL-2 received doses of IL-2 totalling 3 to 18 million international units per day during five-day treatment cycles, followed by a rest period of at least eight weeks before the next treatment cycle.
At the time samples were taken from the study patients, all 26 had plasma viral loads that were less than 50 HIV copies per millilitre (ml) of blood.
In six of the 14 HIV-infected individuals receiving IL-2 plus HAART, the NIAID researchers did not detect any HIV capable of replicating when they cultured 10 to 20 million peripheral blood resting CD4+ T cells from each patient. When they cultured much larger numbers of peripheral blood resting CD4+ T cells from these six individuals - up to 330 million cells per person - the researchers still could not find any replication-competent virus in three patients. In contrast, the investigators consistently have found replication-competent HIV in peripheral blood resting CD4+ T cells from each of 12 patients who received HAART alone.
The researchers then performed a lymph node biopsy on one of the three patients treated with IL-2 plus HAART in whom no virus was found in peripheral blood resting CD4+ T cells. Replication-competent HIV could not be isolated from the lymph node tissue that they examined.
"Our new data suggest that in HAART- treated patients, interleukin-2 may have a role in reducing this 'reservoir' of virus, where HIV would otherwise remain sequestered from the immune system," says Dr. Fauci.
Scientists believe that other hidden reservoirs of HIV exist, and may include the brain, testes, CD4+ T cells in other lymphoid organs such as the gut, and other immune system cells such as macrophages. Together, these potential viral sanctuaries pose a formidable obstacle to the ultimate control or eradication of HIV from an infected person's body.
Investigators at NIAID and elsewhere are developing strategies to diminish the amount of virus in these hiding places, speculating that a smaller pool of latently infected cells would more likely be controlled by the immune system of the patient.
"We look forward to extending and elaborating on these observations," says Dr. Fauci. "In particular, we hope to determine the mechanisms of the observed effects, which currently are unclear. It will also be crucial to determine the clinical relevance of reducing the size of the latently infected resting CD4+ T- cell pool.
"The final proof of the feasibility of effectively controlling replication-competent HIV in latently infected cells will be discontinuation of HAART and long-term follow-up," Dr. Fauci notes.
Source: NIH NEWS
In-Vivo Anti-CD3-Induced HIV-1 Viraemia
Researchers from the University Hospital Nijmegen in the Netherlands and the University Hospital Utrecht describe the administration of monoclonal antibodies to CD3 cells in an HIV- 1 infected liver transplant patient who had refused antiretroviral therapy. Treatment with antibodies to CD3 cells is considered a possible option for the activation of cells latently infected with HIV-1. Cell activation combined with antiretroviral treatment may be a method of clearing the virus for the body; but, it is not known if the administration of these antibodies results in HIV-1 proliferation in vivo. In the liver transplant patient, treatment with the monoclonal antibodies to CD3 resulted in a time-dependent six-fold increase in viral load, without adverse effects. The viral load returned to pre-treatment levels after the seven day treatment. According to the authors, the findings demonstrate the feasibility of in vivo activation of HIV-1 replication with antibodies to CD3, although it is not clear to what extent latently infected cells helped boost viral load.
Ref: Brinkman, K.; Huysmans, F.; Galama, J.M.D. et al. Lancet (31/10/98) Vol. 352, No. 9138, P. 1446.
Source: CDC HIV/STD/TB Prevention News Update
US FDA Approval of Abacavir Recommended
An advisory committee to the US Food and Drug Administration (FDA) has recommended accelerated approval for the new drug abacavir (ABC, Ziagen). Abacavir works by attacking the viral enzyme RT (reverse transcriptase), and is related to other drugs such as AZT, 3TC, d4T, ddI and ddC. The drug is supplied in 300 mg tablets, and is meant to be taken twice daily in combination with other anti-HIV agents.
The manufacturer of ABC, Glaxo- Wellcome, presented data to the committee on the use of abacavir in combination with 2 of the company's other products, namely AZT and 3TC. In one study, 86% of subjects on ABC/AZT/3TC had their viral loads fall to fewer than 400 copies/ml compared to only 43% on AZT/3TC. However, CD4+ cell counts increased to similar levels in both groups, perhaps because many subjects had been exposed to antiviral drugs before entering this study. The ABC-containing regimen also boosted CD4+ cell counts in children.
In the third study, ABC/AZT/3TC was tested against a combination of the protease inhibitor indinavir with AZT/3TC in 562 subjects. After 4 months, 60% of subjects in both groups had viral levels below 400 copies/ml. By the 6th month of the study, 24% of subjects had dropped out, which raised concerns about the reliability of the data. Results from this study will need to be carefully analysed before accurate claims about the long-term efficacy of ABC can be made.
Indeed, the vote to recommend approval was not unanimous; 2 of the 7 panellists voted against such a recommendation citing concerns which included drug toxicity.
About 3% of subjects who used ABC in clinical trials experienced a hypersensitivity reaction with symptoms that included rash, nausea, fever and tiredness. This reaction was most likely to occur during the first 5-6 weeks of use, and often caused people to stop taking the drug. Once this happens, there is a great danger that if the drug is restarted, a fatal reaction to ABC may occur. In fact, the FDA has concluded that at least 8 people have died due to complications from this hypersensitivity reaction.
Source: "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca"
Potent Suppression of HIV-1 Replication in Humans by T-20, a Peptide Inhibitor of Gp41- Mediated Virus Entry
Researchers from the University of Alabama at Birmingham, and elsewhere report that the peptide inhibitor T-20 can significantly reduce plasma HIV RNA levels in patients. T-20 inhibits HIV from entering into target cells by hindering the gp41 protein on the virus, according to the proposed mechanisms of drug action. The scientists administered the drug to 16 patients in four different dose groupings. The patients received T-20 twice a day at levels of 3 mg, 10 mg, 30 mg, or 100 mg intravenously over 14 days. Patients in the highest dosage group showed reductions in plasma HIV RNA of 99 percent, with no significant drug-related side effects. The authors note that "the findings provide proof-of-concept for new therapeutics targeting this essential step [HIV-1 fusion and entry in humans] in the life-cycle of HIV and other fusogenic, enveloped viruses," adding that the method of action by T-20 constitutes a new class of antiviral therapy that shows potent activity in vivo. While the drug is not likely to be cross resistant with other available antiviral agents, they note that further studies are underway to determine resistance.
Ref: ; Kilby, J. Michael; Hopkins, Sam; Venetta, Thomas M.; et al. Nature Medicine (11/98) Vol. 4, No. 11, P. 1302 Source: CDC HIV/STD/TB Prevention News Update
|
In an accompanying editorial (Nature Medicine (11/98) Vol. 4, No. 11, P. 1232) Douglas D. Richman of the University of California at San Diego, notes that there are still a number of issues to be resolved in the use of the drug. In Nature Medicine, Richman explains that T-20 is a synthetic, 36-amino- acid peptide that is thought to interfere with the gp41 protein, thereby preventing HIV access to target cells. The author notes that much further investigation on the drug is needed to determine long-term tolerance and toxicity. The durability of the drug must be assessed since one or two mutations in the target sequence of gp41 are enough to confer viral resistance. Also, administration is a problem since the molecular size of the drug makes it impossible for oral absorption. The drug's hydrophobicity also raises concerns about its distribution in the genital tract and central nervous system, although Richman adds that "any new drug that shows promise against HIV is very welcome."
|
Nevirapine - Caution for Chinese?
One of the side effects associated with the use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) is rash. In rare cases, the rash caused by nevirapine can be fatal. Clinical studies of nevirapine have primarily involved white males. As a result, little data is available to indicate whether the risk of rash is greater in different ethnic groups.
However, doctors in Hong Kong now report 5 cases of severe rash among 8 patients given nevirapine. The rash in question failed to clear despite treatment with antihistamines, so the patients had to stop taking the drug.
Interestingly, 3 of them had never used anti- HIV drugs before. Two of the patients were female, and all were ethnic Chinese. It is not clear why there was such a high incidence of rash in these people, but the Hong Kong doctors urge that physicians keep this in mind when prescribing nevirapine to their HIV-positive patients of Chinese origin. Ref: AIDS 1998;12(15):2082-2083.
Source: "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca"
UK Human Rights Act will allow challenges to treatment refusals
The Human Rights Act received royal assent in Britain this week, paving the way for patients to challenge the refusal of medical treatments on cost grounds.
For the first time, British people will have the right to enforce a range of civil and political rights in their own courts, sparing them the long trek to the European Court of Human Rights in Strasbourg. The act incorporates into UK law the European Convention on Human Rights, which guarantees a range of rights, including the right to life and to respect for private and family life, and the right to freedom from inhuman and degrading treatment and freedom from arbitrary detention. Implementation of the act is certain to bring issues of NHS resources and healthcare rationing to the fore. Judges' powers under judicial review--the means by which treatments are challenged--are currently very narrow but will become much wider under the act. Ian Kennedy, professor of health law, ethics, and policy at University College London, suggested that resource allocation in the NHS might be "the first area of collision between the courts and the government" once the act is in force. Patients denied expensive treatments on cost grounds may invoke right to life arguments.
The same day that the act was given royal assent, three transsexuals took North West Lancashire health authority to court to try to force it to fund their sex change operations. The three will not be able to invoke the act, but only because it is not yet in force. Implementation is being delayed, probably until 2000, to allow judges to be trained and public authorities to review the way they carry out their functions. Under the act, transsexuals refused funding for surgery could argue that this breaches their right to respect for private and family life.
Author: Clare Dyer, legal correspondent, BMJ Ref: BMJ 1998;317:1339 (14th November 1998)