Medical Consultant
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Fourth International Congress on Drug Therapy in HIV Infection (Part 2)8-12 November 1998 - Glasgow, Scotland
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Fourth International Congress on Drug Therapy in HIV Infection8-12 November 1998 - Glasgow, Scotland
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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: http://www.healthcg.com/hiv/
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.
Author: Dr Graeme Moyle Source: Clinical Care Options for HIV, http://www.healthcg.com/hiv/
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OTHER NEWS
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For years, HIV-1 treatment strategies have been based on the dogma "it's the virus, stupid". The result of this dogma was highly active antiretroviral therapy (HAART). But while HAART has revolutionised treatment of HIV-1 disease, it is not perfect and experts are now thinking about the other side of the equation. "HIV is a disease of the immune system", emphasises David Cooper (University of New South Wales, Sydney, Australia). Thus, immune-based therapies are now being revisited to improve HAART efficacy.
If HIV-1-infected patients are treated early and effectively with HAART, when immunity is not irreversibly damaged, the immune system will probably recover, says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID; Bethesda, MD, USA). But many people do not get treated that early. And even if HAART boosts CD4-cell counts, the ability to control HIV-1 itself is not restored by HAART, warns Joseph Kovacs (NIAID). Long-lived, quiescent CD4 memory cells can be reservoirs for latent HIV-1 and if HAART is reduced, the virus may be reactivated. Thus, combining HAART with strategies to boost immunity and enhance specific anti-HIV-1 responses might improve outcomes.
"Patients with HIV infection don't get sick unless their CD4 T-cell counts decline", explains Clifford Lane (NIAID). "IL-2 [interleukin-2] is the only treatment I know of right now that directly expands the CD4 T-cell pool to any degree." Lane and Kovacs have shown that IL-2 can increase and maintain CD4 counts. But is clinical outcome improved? To find out, an international group led by Cooper and Donald Abrams (University of California at San Francisco, CA, USA) has proposed ESPRIT--a phase III study of subcutaneous IL-2 in antiretroviral-treated patients. The trial, which Cooper discussed at the IVth International Congress of Drug Therapy in HIV Infection (Glasgow, UK; Nov 8-12), may also add to evidence from a pooled analysis of randomised trials which indicates that IL-2 may have antiviral effects. "The mechanism is not clear but may be related to improved efficacy of CD8 cells", suggests Kovacs.
IL-2 also induces proinflammatory cytokine production, which might enhance HIV-1 expression in latently infected cells. Surprisingly, this action may be beneficial. As Fauci explains, stimulated reservoir cells might "spit out the virus and die", and HAART given at the same time should stop released virions infecting other cells. "If you can do this repeatedly over time, you may whittle away at the reservoir of latently infected cells", speculates Lane. Data presented by Fauci on Nov 15 at the 36th Annual Meeting of the Infectious Diseases Society of America (Denver, CO, USA) support this hypothesis.
Infusion of antibodies or histocompatible lymphocytes may be another way to enhance immunity. Robert Walker (NIAID) and Lane are studying whether intensive lymphocyte transfers from a healthy twin can restore broad immunity in an HIV-1-infected twin. Several groups are extending this strategy by making virus-specific T cells. The NIAID team, together with Cell Genesys (Foster City, CA, USA), have genetically modified CD8 cells so that they specifically kill HIV-1-infected cells. The cells carry a chimeric receptor consisting of a CD4 molecule joined to the chain of CD3. When the CD4 molecule binds HIV-1 gp120 on a target-cell surface, the engineered CD8 cell is directly activated via CD3. Preliminary studies suggest that modified T-cells persist and migrate to gastrointestinal lymphoid tissue, an important HIV-1 reservoir. Cell Genesys are now planning to test whether their modified cells are active against HIV-1 reservoir cells.
But even if T-cell infusions succeed in enhancing immunity, the approach may not be feasible for treating large numbers of people, warns Fauci. Therapeutic immunisation with HIV-1 antigens or DNA may be more practical. Frances Gotch (Chelsea and Westminster Hospital, London, UK) believes that Remune (Immune Response Corp, Carlsbad, CA, USA)--killed, gp120-depleted HIV-1 mixed with incomplete Freund's adjuvant--is the "best candidate vaccine" for further study. Data presented in Glasgow suggest that Remune can induce HIV-1-specific immune responses that are of the same magnitude as those seen in HIV-1-positive people with non-progressive disease. An ongoing phase III study--the first to test an immune strategy--will show whether these responses translate into clinical benefit. Another approach currently being tested by Gotch in the Chelsea Immunotherapy Study involves the addition of IL-2 to Remune to enhance HIV-1-specific responses.
Paradoxically, inhibition of the aberrant immune activation that occurs in HIV-1 disease may also be beneficial. "A persistently activated immune system is bad news for containing the virus and for protective immune responses", notes Leonard Calabrese (Cleveland Clinic, OH, USA). He and others believe that, if the balance is right, immunosuppressants might improve virological control and reduce virally induced immunosuppression. Calabrese is investigating whether low-dose cyclosporine could be used to control immune activation without adverse effects. NIAID scientists are already investigating whether regimens such as IL-2 plus prednisone or IL-2 plus TNF antagonists reduce the side-effects associated with IL-2 therapy.
While such multimodal strategies seem increasingly likely, there is still controversy about which combinations will work. Some experts believe, for example, that immunisation will not produce effective responses unless immune hyperactivity is controlled. What is clear, however, is that experience with HAART has brought a more balanced approach to the treatment of HIV-1 disease. "Most people agree now that it isn't 'just the virus, stupid'", concludes Fauci.
Ref: Lancet: Volume 352, Number 9141 21 November 1998 Author: Kelly Morris
The AIDS Clinical Trial Group Protocol 076 showed that zidovudine monotherapy reduced the risk of vertical HIV transmission. Analysis indicates, though, that maternal HIV titres were only marginally reduced, suggesting that zidovudine exerts its effect through another mechanism, such as postexposure prophylaxis in utero or possibly during birth. This fostered hope that a short course of zidovudine--one administered just before or during birth--could prevent HIV transmission. A new study in the New England Journal of Medicine shows that zidovudine administered soon after exposure in the child, but not the mother, had a preventative effect. In an editorial in the New England Journal of Medicine, Dr. Kenneth McIntosh of Children's Hospital in Boston, examines the ramifications of these findings, particularly the recent study showing the efficacy of postexposure prophylaxis with zidovudine. McIntosh questions the results since there was a wide degree of confidence intervals. He also wonders whether the results can be confirmed since a recreation of the study would have ethical problems. McIntosh notes, however, that the study adds further "weight to the argument that HIV infection can be prevented after exposure," even without additional confirmation.
Ref: McIntosh, Kenneth. New England Journal of Medicine (11/12/98) Vol. 339, No. 20, P. 1467 Source: CDC HIV/STD/TB Prevention News Update
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These findings have obvious implications for the use of zidovudine in resource poor settings. They also underscore the benefits of HIV testing during pregnancy. Obviously antiviral intervention, even if limited to just before or after birth, can only happen if the HIV-infection is discovered. The implication that zidovudine given up to 48 hours after birth reduced risk of transmission also underlines the possibilities of post-exposure prophylaxis in other settings ie. post-sexual exposure. If zidovudine monotherapy shows efficacy with administration at such a late time point we may reasonably expect even better rates of prevention with administration of multiple agents in combination - especially those that are active in their administered form.
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According to a study appearing in the November issue of the American Journal of Respiratory Critical Care, cigarette smoking may suppress the percentage and absolute number of CD4 and CD8 cells in the bronchoalveolar lavage fluid in HIV-positive patients, which may in turn cause a decrease in lung defenses against infection. Dr. Mark D. Wewers and others at Ohio State University analysed the effect of smoking on 92 HIV-positive subjects, finding that the smokers in the cohort had reduced percentages and absolute numbers of lung lymphocytes. There was also an increased number of alveolar macrophages and suppression of pro-inflammatory cytokines interleukin-1-beta and tumour necrosis factor-alpha production. The authors concluded that smoking creates a suppressive lung inflammatory environment in HIV-infected individuals and that the cessation of smoking in these patients may be important.
Source: CDC HIV/STD/TB Prevention News Update
Abstract
To investigate the incidence and demographics of gastric hypoacidity among persons infected with human immunodeficiency virus (HIV), 146 asymptomatic subjects were evaluated with use of a radiotelemetry device (Heidelberg capsule). Gastric hypoacidity (minimum gastric pH of greater than or equal to 3) occurred in 24 subjects (17%). Demographic characteristics, CD4 cell counts, and Helicobacter pylori serological status were evaluated for an association with gastric pH. Subjects with hypoacidity were more likely to have positive H. pylori serology than were subjects without hypoacidity (15 of 24 vs. 23 of 74, respectively; P = .004), Multivariate analysis indicated that a positive H. pylori serology was the most significant predictor of hypoacidity, accounting for an increase in gastric pH of 39%. A history of injection drug use, heterosexual transmission of HIV, and male gender were also associated with an elevated gastric pH, CD4 cell counts did not contribute to predictions of gastric pH. A history of H. pylori infection is relatively common in HIV-positive black and Hispanic populations and is a predictor of gastric pH.
Ref: Shelton,M.J., Adams,J.M., Hewitt,R.G., Morse,G.D.: Clin.Infect.Dis.,27 (4):739-745 (1998 Oct)
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Previous studies have also revealed an increased incidence of hypoacidity in HIV-infection, this is the first to link this with an increased incidence of H. pylori infection. Hypoacidity (at least secondary to ddI, H2 receptor antagonists and proton pump inhibitors) may affect absorption and exposure to indinavir and thus may influence activity. Screening for H. pylori infection is problematic but if this infection is chronic and widespread amongst those with HIV perhaps Helicobacter eradication regimens should be offered to all and also contemplated before initiation of combination antiretrovirals.
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Researchers for the Terry Beirn Community Programs for Clinical Research on AIDS report on the use of standardised acupuncture regimen (SAR) and amitriptyline hydrochloride for HIV-related peripheral neuropathy pain relief. They conducted a modified, double-blind factorial comparison of SAR, amitriptyline, or the combination of both against placebo. They also evaluated SAR versus control points and amitriptyline against placebo. Using a daily recorded pain scale and changes in mean pain scores at six and 14 weeks, the authors found that neither acupuncture nor amitriptyline was more effective than placebo in relieving the pain caused by HIV-associated peripheral neuropathy.
Abstract
Context.-Peripheral neuropathy is common in persons infected with the human immunodeficiency virus (HIV) but few data on symptomatic treatment are available.
Objective.-To evaluate the efficacy of a standardized acupuncture regimen (SAR) and amitriptyline hydrochloride for the relief of pain due to HIV-related peripheral neuropathy in HIV-infected patients.
Design.-Randomized, placebo-controlled, multicenter clinical trial. Each site enrolled patients into 1 of the following 3 options: (1) a modified double-blind 2_2 factorial design of SAR, amitriptyline, or the combination compared with placebo, (2) a modified double-blind design of an SAR vs control points, or (3) a double-blind design of amitriptyline vs placebo.
Setting.-Terry Beirn Community Programs for Clinical Research on AIDS (HIV primary care providers) in 10 US cities.
Patients.-Patients with HIV-associated, symptomatic, lower-extremity peripheral neuropathy. Of 250 patients enrolled, 239 were in the acupuncture comparison (125 in the factorial option and 114 in the SAR option vs control points option), and 136 patients were in the amitriptyline comparison (125 in the factorial option and 11 in amitriptyline option vs placebo option).
Interventions.-Standarized acupuncture regimen vs control points, amitriptyline (75 mg/d) vs placebo, or both for 14 weeks.
Main Outcome Measure.- Changes in mean pain scores at 6 and 14 weeks, using a pain scale ranging from 0.0 (no pain) to 1.75 (extremely intense), recorded daily.
Results.-Patients in all 4 groups showed reduction in mean pain scores at 6 and 14 weeks compared with baseline values. For both the acupuncture and amitriptyline comparisons, changes in pain score were not significantly different between the 2 groups. At 6 weeks, the estimated difference in pain reduction for patients in the SAR group compared with those in the control points group (a negative value indicates a greater reduction for the "active" treatment) was 0.01 (95% confidence interval [CI], -0.11 to 0.12; P =.88) and for patients in the amitriptyline group vs those in the placebo group was -0.07 (95% CI, -0.22 to 0.08; P =.38). At 14 weeks, the difference for those in the SAR group compared with those in the control points group was -0.08 (95% CI, -0.21 to 0.06; P=.26) and for amitriptyline compared with placebo was 0.00 (95% CI, -0.18 to 0.19; P =.99).
Conclusions.-In this study, neither acupuncture nor amitriptyline was more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.
Ref: Shlay, Judith C.; Chaloner, Kathryn; Max, Mitchell B.; et al. Journal of the American Medical Association (11/11/98) Vol. 280, No. 18, P. 1590; Source: CDC HIV/STD/TB Prevention News Update
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The authors of this study conclude..."this is the largest reported randomised, placebo-controlled, clinical trial of symptomatic treatment for HIV-related peripheral neuropathy. Overall, our results indicate that neither this SAR given over 14 weeks nor amitriptyline hydrochloride, 75 mg/d, was effective in relieving pain and neither therapy can be recommended for the treatment of HIV-related peripheral neuropathy. Additional clinical trials are needed because there are no effective treatments for this chronic debilitating condition." Gabapentin - an antiepileptic drug also being investigated for post herpetic neuralgia appears to be a good candidate for further investigation in peripheral neuropathy. L-acetyl carnitine, a form of amino acid, has also been found to be below normal levels in neuropathic nerves so supplementation is being tried. The difficulties in managing peripheral neuropathy in the setting of HIV-disease emphasise the need for rapid identification and suspension of any drugs which may be suspected of neurotoxicity. Rapid response to onset remains a key issue to stop a manageable and usually promptly resolving grade 1 peripheral neuropathy from becoming a disabling irreversible grade 3 - 4.
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The Food and Drug Administration approved nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), for use in HIV-infected children. Nevirapine is the first NNRTI to be approved for children. Clinical trials showed the drug to effectively suppress HIV-1 viral load in children and to be well tolerated, although one study found that 16 percent of children on the drug developed a related rash. The drug is manufactured by Roxane Laboratories in the U.S.
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In safety data accumulated from a number of paediatric use studies incidence or severity of rash does not appear to be any greater than that seen with adult use. Granulocytopaenia has been seen with the use of nevirapine in children and was reported as severe in 2% of children receiving nevirapine in the ACTG245 trial.
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Abstract
OBJECTIVE: To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterise MddNR strains genotypically and phenotypically.
DESIGN AND METHODS: Blood samples from patients after > or = 6 months of treatment with multiple ddN were screened for the MddNR mutation Q151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients.
RESULTS: The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations.
CONCLUSIONS: MddNR resistant HIV-1 can be found in European patients. MddNR is characterised by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.
Ref: AIDS 1998 Oct 22;12(15):2007-15
Scientists have isolated an HIV-1 strain that reportedly can confer resistance to most or all nucleoside reverse transcriptase inhibitors. Their study, published in the Nov. 15 issue of the Journal of Clinical Investigation, isolated 14 strains of HIV-1 containing a six-basepair insert in the reverse transcriptase gene. The strains were present in 10 of 1,045 HIV patients genotyped between August 1997 and July 1998. The authors note that the finding poses problems for treatment strategies in patients with the mutation.
Abstract While many point mutations in the HIV-1 reverse transcriptase (RT) confer resistance to antiretroviral drugs, inserts or deletions in this gene have not been previously characterised. In this report, 14 RT inhibitor-treated patients were found to have HIV-1 strains possessing a 6-basepair insert between codons 69 and 70 of the RT gene. Known drug resistance mutations were also observed in these strains, with T215Y appearing in all strains. Genotypic analysis indicated that the inserts had substantial nucleotide variability that resulted in relatively restricted sets of amino acid sequences. Linkage of patients' treatment histories with longitudinal sequencing data showed that insert strains appeared during drug regimens containing ddI or ddC, with prior or concurrent AZT treatment. Drug susceptibility tests of recombinant patient isolates showed reduced susceptibility to nearly all nucleoside RT inhibitors. Site-directed mutagenesis studies confirmed the role of the inserts alone in conferring reduced susceptibility to most RT inhibitors. The addition of AZT-associated drug resistance mutations further increased the range and magnitude of resistance. These results establish that inserts, like point mutations, are selected in vivo during antiretroviral therapy and provide resistance to multiple nucleoside analogues.
Ref: Winters MA, Coolley KL, Girard YA, Levee DJ, Hamdan H, Shafer RW, Katzenstein DA, and Merigan TC. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. Journal of Clinical Investigation 1998 Nov 15;102:1769-1775.
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Management of patients with resistance to multiple nucleoside analogues is a real problem. Most have also been exposed to PI's and NNRTI's so have only one remaining class - the nucleoTIDE analogues. Adefovir or PMPA may have some activity on some of these backgrounds but would obviously need support for any durable effect. Access to more experimental compounds such as T-20 should be explored as well as recycling nucleosides with hydroxyurea to formulate novel combinations. New mutations or sets of mutations are emerging so the reported 3.5% here looks likely to be an underestimate of what will be faced in clinical practice. What needs further understanding is which nucleosides select for these backgrounds most readily so that they would not be so readily used in earlier combinations. It may only reflect more widespread use of a longer duration - but current data strongly suggests that zidovudine associated genotypic mutations are a key element in the multiply nucleoside resistant HIV characterised so far. |