Contents
|
ATP Dr FAX SYMPOSIUM RESISTANCE ASSAYS IN CLINICAL PRACTICE22nd October 1998, London (Summary Report)
|
- More Data Published on Induction Maintenance Strategies
- Highly Active Antiretroviral Therapy Normalises the Function of Progenitor Cells in Human
Immunodeficiency Virus-Infected Patients.
- New Evidence for Thymic Reactivation in Adults on HAART
- No Additional Toxicity's or Adverse Events seen with Inclusion of Lamivudine in paediatric HIV
combination regimens
- Accelerating Decay of the Third Compartment - Kill or Cure?
- Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease8
- Activation and Cell Cycle Antigens in CD4+ and CD8+ T Cells Correlate with Plasma Human
Immunodeficiency Virus (HIV-1) RNA Level in HIV-1 Infection.
- Frequent HIV Reinfection Demonstrated in Chimpanzees.
- Changes in lymphocyte subsets in human immunodeficiency virus-positive persons with <5 CD4 T
lymphocytes/mm3.
- Major surgery seems not to influence HIV disease progression in haemophilia patients
- Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte
responses in HIV+ patients
- Eradication of AIDS-Related Disseminated Mycobacterium avium Complex Infection after 12
Months of Antimycobacterial Therapy Combined with Highly Active Antiretroviral Therapy.
ON THE WEB
- Genetic Database for Sexually Transmitted Diseases Goes Online
- Comprehensive Aspergillus Website Opens
- MMWR Recommendations and Reports --- Prevention and Treatment of Tuberculosis Among
Patients Infected with Human Immunodeficiency Virus: Principles of Therapy and Revised
Recommendations
Antiretroviral Drugs and Treatment Strategies |
More Data Published on Induction Maintenance Strategies
"A Randomised Trial of Three
Maintenance Regimens Given After Three
Months of Induction Therapy With Zidovudine,
Lamivudine, and Indinavir in Previously
Untreated HIV-1-Infected Patients"
Two-drug maintenance therapy following a three-month regimen of triple-drug therapy for HIV-positive individuals is less effective than continuation of the triple-drug therapy, according to French researchers. To determine whether problems related to compliance and tolerability could be reduced through the administration of a two-drug regimen rather than a three-drug regimen, researchers from the Trilege Study Team investigated maintenance programs on viral suppression in 378 patients. The patients, who were antiretroviral naive, received three months of induction treatment with lamivudine, zidovudine, and indinavir.
Of the initial patients, 279 had plasma HIV- 1 RNA levels fall below 500 copies per cubic millimetre after two months. These patients were then assigned to either continued triple- drug therapy or two-drug maintenance therapy with zidovudine and lamivudine or zidovudine and indinavir. The researchers observed that 31 percent of the patients receiving zidovudine plus lamivudine and 21 percent of those on zidovudine plus indinavir had virologic failure. Comparatively, 9 percent of patients who continued triple-drug therapy experienced virologic failure. The authors note that among patients who switched to dual-therapy, even those subjects with maximally suppressed HIV-1 RNA (defined as less than 50 copies per millimetre) had a higher failure rate.
The scientists concluded that two-drug therapy is less effective in sustaining a reduced viral load than triple-drug therapy.
Source: CDC HIV/STD/TB Prevention News
Update
Ref: Pialoux, Gilles; Raffi, Francois; Brun-
Vezinet, Francoise; et al. New England Journal
of Medicine (29/10/98) Vol. 339, No. 18, P.
1269;
Abstract
Background. The long-term effectiveness of
potent three-drug antiretroviral regimens for the
treatment of human immunodeficiency virus
type 1 (HIV-1) infection is limited by problems
related to compliance and tolerability. We
investigated whether two-drug maintenance
therapy would suppress viral replication after a
three-month period of aggressive triple-drug
induction therapy.
Methods. A total of 378 HIV-1-infected adults who had not received previous antiretroviral treatment received three months of induction therapy consisting of 300 mg of zidovudine every 12 hours, 150 mg of lamivudine every 12 hours, and 800 mg of indinavir every 8 hours. The 279 patients in whom the plasma HIV-1 RNA titre fell below 500 copies per millilitre after two months of triple-drug therapy, and who completed the induction phase, were randomly assigned at month 3 to one of the following three open-label maintenance regimens: zidovudine, lamivudine, and indinavir; zidovudine and lamivudine; or zidovudine and indinavir. The primary end point was an increase in HIV-1 RNA levels to 500 copies or more per millilitre during the maintenance phase.
Results. The proportion of patients who reached the primary end point was significantly higher among patients receiving zidovudine plus lamivudine (29 of 93 patients, P<0.001) or zidovudine plus indinavir (21 of 94, P=0.01) than among patients receiving continued triple- drug therapy (8 of 92). This higher failure rate in the groups treated with the two-drug maintenance regimens was also observed in the subgroup of patients with maximally suppressed HIV-1 RNA (below 50 copies per millilitre) at the time of randomisation to maintenance therapy.
Conclusions. In HIV-1-infected adults not previously treated with antiretroviral drugs whose plasma HIV-1 RNA levels fell below 500 copies per millilitre after three months of induction therapy with zidovudine, lamivudine, and indinavir, two-drug maintenance therapy was less effective in sustaining a reduced viral load than continued three-drug therapy.
"Maintenance Antiretroviral Therapies in HIV-Infected Subjects with Undetectable Plasma HIV RNA after Triple-Drug Therapy"
Researchers for the AIDS Clinical Trials Group Study 343 Team report that triple-drug therapy with indinavir, lamivudine, and zidovudine better sustains the suppression of plasma HIV RNA in HIV-positive patients than maintenance therapy with indinavir alone or a combination of zidovudine and lamivudine. The researchers, led by Dr. Diane V. Havlir of the University of California at San Diego, investigated less intensive maintenance programs among patients who had achieved plasma HIV viral loads of less than 200 copies/mL following triple-drug therapy. The patients were divided into three groups: 106 continued triple-drug therapy, 103 received monotherapy with indinavir, and 107 subjects received zidovudine and lamivudine. Only 4 percent of patients maintaining triple-drug therapy lost viral suppression (defined as a plasma level of at least 200 copies of HIV RNA per millimetre on two consecutive measurements during therapy), with 23 percent of monotherapy subjects and 23 percent of dual-therapy patients showing loss of viral suppression. Those at higher risk for loss of viral suppression had greater increases in CD4 cell counts during induction therapy, higher viral loads at baseline, and slower rates of viral clearance. The authors also note that zidovudine-resistance mutations in HIV RNA at baseline were strongly predictive of viral suppression loss in patients receiving the dual therapy of zidovudine and lamivudine.
Source: CDC HIV/STD/TB Prevention News Update
Ref: Havlir, Diane V.; Marschner, Ian C.; Hirsch,
Martin S.; et al. New England Journal of
Medicine (29/10/98) Vol. 339, No. 18, P. 1261.
Abstract
Background. Combination antiretroviral
therapy with indinavir, zidovudine, and
lamivudine can suppress the level of human
immunodeficiency virus (HIV) RNA in plasma
below the threshold of detection for two years or
more. We investigated whether a less intensive
maintenance regimen could sustain viral
suppression after an initial response to
combination therapy.
Methods. HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimetre, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per millilitre of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per millilitre on two consecutive measurements during maintenance therapy.
Results. During maintenance treatment, 23 percent of the subjects receiving indinavir and 23 percent of those receiving zidovudine and lamivudine, but only 4 percent of those receiving all three drugs, had loss of viral suppression (P<0.001 for the comparison between triple-drug therapy and the other two maintenance regimens). Subjects with greater increases in CD4 cell counts during induction therapy, higher viral loads at base line (i.e., at the beginning of induction therapy), and slower rates of viral clearance were at greater risk for loss of viral suppression. The presence of zidovudine-resistance mutations in HIV RNA at base line was strongly predictive of the loss of viral suppression in subjects treated with zidovudine and lamivudine.
Conclusions. The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavir alone or zidovudine and lamivudine.
|
These two studies, Trilege and ACTG 343, together with the ADAM study published earlier this year all indicate that deintensifying protease inhibitor based combination regimens after 24 weeks in persons who are plasma HIV-1 viral RNA undetectable by any available assays is not a prudent approach. The reasons for the loss of virologic control in the maintenance phases of these trials are unclear and likely to be mixed. Limited data from newer assays which detect down to 5 copies/mL RNA suggest detectable HIV RNA production may be occurring in many responders to HAART. Lymph node data also suggest continued viral replication at this site long after undetectable HIV RNA is achieved in the plasma. These data do not rule out the possibility of deintensification (the majority of trial participants DID continue to maintain suppression during the maintenance phases) but it remains to be able to characterise who will succeed rather that fail on maintenance and to ensure that such successful maintenance is of a useful durability. Other approaches to long term therapy such as substitution of the PI with an NNRTI, triple nucleoside analogues, the inclusion of hydroxyurea and a combined antiretroviral/immunotherapy approach would also warrant further investigation. In an accompanying editorial David Cooper and Sean Emery of the University of New South Wales also comment on the observation in the ACTG study that the size of the increases in the CD4 cell count during induction therapy was inversely correlated with the probability of subsequent maintenance of remission. The authors of the ACTG paper propose a predator- prey hypothesis to explain this apparent paradox similar to the target cell availability hypothesis elaborated by Angela McClean (reported in Issue 53 of ATPs DocFax). The editorial also raises the challenging idea (challenging to the treat-early brigade of activists, patients, clinicians and pharmaceutical companies) of comparing strategies of early, potent antiretroviral therapy with deferred therapy for HIV-1 infection.
|
Highly Active Antiretroviral Therapy Normalises the Function of Progenitor Cells in Human Immunodeficiency Virus-Infected Patients.
CD34 cells from human immunodeficiency virus (HIV)-infected persons have been described to be impaired in function. The effect of highly active antiretroviral treatment (HAART) on the function of CD34 cells in HIV- infected patients was examined. Numbers and function of CD34 cells from 11 HIV- infected patients were determined prior to HAART and after 2, 4, 8, and 12 weeks of therapy. The mean number of colony-forming units (cells) per millilitre (cfu/mL) was 15.0 prior to HAART vs. 109.8 in healthy controls (P<.001). During HAART, the number of cfu/mL increased to 100.3 (P<.001).
This increase in cfu/mL eliminated the differences between HIV-infected patients and controls. Significant increases in numbers of CD34 cells were not detected. Of importance, the cloning efficiency of CD34 cells increased from 1.7% prior to therapy to a peak at 18.7% (P=.003). In conclusion, HAART normalised CD34 cell function in HIV-infected patients and thus might allow de novo production of T lymphocytes from progenitor cells. Ref: Dam Nielsen S, Kjar Ersboll A, Mathiesen L, Nielsen JO, Hansen JE. J Infect Dis 1998 Nov;178 (5):1299-1305.
|
While the data on de novo production of lymphocytes in this and the following study are encouraging it has to be emphasised that these patients were receiving protease inhibitor based HAART. With greater use of NNRTI based regimens and suggestions of their equivalence in terms of viral suppression, it is now crucial to perform similar investigations of immune function after maximally suppressive NNRTI based therapy. Along with evidence (currently lacking) of remission of opportunistic illnesses such as Kaposis sarcoma and PML such data on immune recovery (not just CD4 cell numbers) will be necessary to allow informed clinical decisions on the role of NNRTI based therapy in comparison to that of PI based. |
New Evidence for Thymic Reactivation in Adults on HAART
Richard Koup of the University of Texas (formerly at Aaron Diamond) developed a new technique for measuring how recently new T cells emigrated from the thymus.
Circular fragments of DNA which are produced in T cells during thymic maturation, known as alpha circles or T cell rearrangement excision circles (TREC), can be used to measure how recently a T cell emerged from the thymus.
Recent thymic emigrants have high levels of TREC, which are formed by excision of DNA fragments during the forming of the T cell receptor during T cell receptor maturation. The TREC DNA fragment copy number is diluted by half with each round of cell division. Therefore, quantitating TREC appears to be a surrogate marker for recent thymic emigration (RTE). People who have had thymectomies have decreases in their amount of TREC, suggesting that thymic activity persists into adulthood.
Koup applied the new assay to the T cells of people receiving HAART and found that as viral load decreased to beneath the limit of quantitation and CD4 counts rise, the amount of TREC in the new CD4 cell population rises as well. This rise is seen exclusively in naive (CD45RA+) T cells, suggesting that they are indeed maturing through the thymic pathway. The TREC increase seen after HAART could only occur if 1) the thymus is active in adults or if 2) lymphocyte receptor maturation happens extrathymically. Koup is now collaborating with Barton Haynes at Duke University to apply the TREC approach to studies of thymic function in HIV infection and other immunologic conditions.
Notes from the Gallo Lab Meeting, 19 September 1998, by Mark Harrington, Treatment Action Group, New York.
No Additional Toxicity's or Adverse Events seen with Inclusion of Lamivudine in Paediatric HIV Combination Regimens
The addition of lamivudine (3TC) to an HIV-infected child's current nucleoside reverse transcriptase inhibitor (NRTI) drug regimen appears to be safe and effective, according to a report by members of the Paediatric European Network for Treatment of AIDS.
There are few data, and no placebo- controlled trials, on the effects of lamivudine in paediatric HIV patients, Dr. D. M. Gibb of the Medical Research Council HIV Clinical Trials Centre in London and colleagues explain. Concerns about toxicity, particularly an increased risk of pancreatitis, in children treated with lamivudine have been raised.
In the current PENTA-4 study, Dr. Gibb's group randomly assigned 162 children who were on stable NRTI therapy to receive placebo or 4 mg/kg twice daily of lamivudine in syrup or tablet form. The children were on the following regimens: zidovudine monotherapy (52 subjects), didanosine (ddI) (39 subjects), zidovudine plus ddI (54 subjects), or zidovudine plus zalcitabine (ddC) (17 subjects).
Most of the children had advanced HIV disease and had been on antiretroviral therapy for about 3 years. The results of up to 72 weeks of follow-up appear in the October 1st issue of AIDS.
Overall, Dr. Gibb's group found that "...serious adverse events were infrequent and similar in the [lamivudine] and in the placebo groups." There were a total of 20 serious adverse events that required the child to drop out of the trial, but these events were seen at about the same frequency in both treatment groups. Only one child, who had very advanced HIV infection and Mycobacterium avium- intracellulare infection, developed pancreatitis.
It is now known that adding a single drug to existing NRTI regimens is "inadequate," the researchers point out, and only 6% of the children in this study achieved undetectable viral loads at 24 weeks. Dr. Gibb's group therefore recommends that, whenever possible, "...children who have been on antiretroviral therapy and are failing should now receive triple therapy regimens with at least two new drugs including a protease inhibitor."
Ref: AIDS 1998;12:F151-F160. Source: CDC HIV/STD/TB Prevention News Update
|
IMMUNOTHERAPY
|
Accelerating Decay of the Third Compartment - Kill or Cure?
Several teams are wasting no time attempting to explore immuno-stimulants which may accelerate decay of the third compartment. At NIH, H. Clifford Lane and Anthony S. Fauci took thirteen patients who had maintained a viral load below the limit of quantification on HAART and administered relatively high-dose interleukin-2 (IL-2). IL-2 is postulated by some to activate resting T cells, although some (e.g., Siliciano) maintain that the resting cell population does not express IL-2 receptors. In any case, Fauci reported that provirally-infected cells could no longer be isolated from three of the 13 IL-2/HAART recipients, even when as many as 300 million cells were extracted. Obviously the "limit of detection" for eradication experiments will be limited by the impossibility of sampling such numbers of cells. Joep Lange of the University of Amsterdam administered an even more daunting regimen of five antiretrovirals plus IL-2 and the mouse monoclonal antibody OKT3, which targets and activates all the body's T lymphocytes through the CD3 receptor. The result is a clinical condition resembling toxic shock, as all the cells release pro-inflammatory cytokines and many die of apoptosis. The hope was that the coadministered HAART would prevent the viruses produced by waking latently infected cells from infecting another generation of cells. While the patients became very sick (requiring admission to the intensive care unit), infectious virus could no longer be cultured from two of the three. One declared himself cured and disappeared from follow-up. However, in both Lange's and Lane's experiments no one has yet to go off HAART. Lane will start enrolling a study at NIH this fall in which anyone who has maintained a CD4 count below 5 copies/mL for over six months will have their antiretroviral therapy terminated. Researchers will then follow the brave volunteers for evidence of viral re-emergence (this approach does not seem to make sense unless the patients have received immunostimulatory therapy). Researchers were reluctant to use the "C-word" in their presentations, but the halls were abuzz with the slightly surreal gossip about very toxic, potentially fatal, possibly curative regimens.
Notes from the Gallo Lab Meeting, 19 September 1998, by Mark Harrington, Treatment Action Group, New York.
Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease
Abstract
Objectives. Therapy of HIV-infection using intravenous interleukin-2 (IL-2) is known to be effective in terms of increasing CD4-counts but is associated with significant side-effects and hospitalisation. However, the combination with protease-inhibitor therapy has not been tested yet. The aim of the present study was to investigate the safety and efficacy of intravenous vs, subcutaneous IL-2 regimes using 9 Mio I.U. of IL-2, in combination with protease-inhibitor therapy.
Design. All patients were treated with a combination of two reverse transcriptase inhibitors and a protease-inhibitor prior to IL-2 administration for at least 6 weeks. Ten patients were assigned to the intravenous IL-2 group (group A), 10 to the subcutaneous group (group B).
Results. In both treatment groups, CD4 count significantly increased shortly after the end of therapy (group A: 223% over baseline [day 7]; group B: 264% over baseline [day 7]). During the follow-up CD4 counts slowly decreased thereafter but remained above baseline 3 months following IL-2 treatment. The CD8 lymphocytes showed a similar but less pronounced pattern with a maximum at day 7 (group A: 116% over baseline, group B: 158% over baseline) and reached baseline earlier in the follow-up-period. Altogether the CD4/CD8- ratio was elevated through long periods on follow-up. Throughout follow-up, there were no apparent changes in viral load during IL-2 therapy in either group. IL-2 therapy was administered for a mean time of 4.2 +/- 0.1 days in the intravenous group and of 4.8 +/- 0.1 days in the subcutaneous group until therapy was terminated at day 5 or due to side effects. Only 1/10 patients completed the 5-day course of intravenous therapy in contrast to 6/10 in the subcutaneous group.
Conclusions. Subcutaneous interleukin-2 using 9 Mio IU day (-1) in combination with protease- inhibitors showed equal efficacy as intravenous therapy and was associated with less side- effects.
Ref: Witzke,O., Winterhagen,T., Reinhardt,W., Heemann,U., Grosse-Wilde,H., Kreuzfelder,E., Roggendorf,M., Philipp,T.: J.Intern.Med.,244 (3):235-240 (1998 Sep)
|
In some studies with the immunomodulator IL- 2, people have received the drug intravenously while in other studies it has been injected subcutaneously. Questions remain as to which route is best. These researchers conducted a study comparing the two modes of administration and found that each was equally effective in raising CD4+ counts but injecting IL-2 under the skin was associated with substantially fewer side effects. Most units conducting studies on IL-2 are moving over to subcutaneous administration - this report provides support for this approach. |
|
PATHOGENESIS
|
Activation and Cell Cycle Antigens in CD4+ and CD8+ T Cells Correlate with Plasma Human Immunodeficiency Virus (HIV-1) RNA Level in HIV-1 Infection.
The relationship between T cell activation and human immunodeficiency virus type 1 (HIV-1) replication was studied in HIV-infected subjects, 20 with and 10 without anti-HIV treatment. Expression of Ki-67 proliferation- associated antigen was increased in CD4+ and CD8+ T cells and correlated with HLA-DR. In subjects without anti-HIV treatment, the plasma HIV-1 RNA level correlated with HLA-DR in CD4+ T cells, with Ki-67 in CD8+ T cells, and with expression of CD38 in both T cell subsets. A proportion of treated subjects had increased T cell activation despite 4 months of highly active antiretroviral treatment (HAART). In subjects receiving HAART, a high percentage of HLA-DR+ CD4+ T cells was associated with signs of opportunistic infections. This work supports the concept that, in the natural course of HIV-1 infection, HIV replication itself leads to general T cell activation and that opportunistic infections generate additional CD4+ T cell activation and HIV replication.
Ref: Orendi JM, Bloem AC, Borleffs JC, Wijnholds FJ, de Vos NM, Nottet HS, Visser MR, Snippe H, Verhoef J, Boucher CA. J Infect Dis 1998 Nov; 178(5):1279-1287
Frequent HIV Reinfection Demonstrated in Chimpanzees.
Addressing an issue plaguing HIV treatment and prevention, Pat Fultz of the University of Alabama at Birmingham (UAB) presented compelling evidence that infection with a primary HIV strain does not prevent subsequent reinfection by another strain in the chimpanzee model. In some animals, both strains were readily detectable at later time points, while in some cases the earlier strain (or strains, in one animal reinfected twice) predominated. The ability to detect superinfection depends on using strain-specific PCR primers (which is not done with standard commercially available viral load assays used in humans). Fultz stated that "when both strains are minimally pathogenic, the first strain predominates in multiple tissues at death," reminding us that "minimally pathogenic" in the chimp is equivalent to an average pathogenic strain in humans (e.g., ten years to clinical disease). This work has chilling implications for the dissemination of drug- resistant HIV strains among individuals already infected. Superinfection is not necessarily detectable by increasing antibody titres, suggesting that there is not always a "booster effect". Fultz achieved 100% (9/9) superinfections within viral clades, and 9/13 between clades.
Notes from the Gallo Lab Meeting, 19 September 1998, by Mark Harrington, Treatment Action Group, New York.
|
Reinfection was also reported at this years ICAAC meeting and would seem to reinforce the message that safe sex amongst HIV-infected people still confers benefit. Clade co-infection in humans was first reported 3-4 years ago but were dismissed as one-offs by those who wished to deny the implications. |
Changes in lymphocyte subsets in human immunodeficiency virus- positive persons with <5 CD4 T lymphocytes/mm3.
Abstract All patients seen at the Royal Free Hospital London, who had at least one CD4 T lymphocyte count of <5 cells/mm3 (n = 166) were prospectively followed to asses changes in their total T lymphocyte and CD8 T lymphocyte counts over time. While overall there were no clear trends towards a drop or increase in either count, persons who died during the study experienced a rapid drop in both CD8 T lymphocyte and total T lymphocyte levels in the months preceding death. Multivariate Cox proportional hazards models revealed that both the total T lymphocyte count and CD8 T lymphocyte count provided important prognostic information for survival. Despite almost a complete absence of CD4 T lymphocytes, lymphocyte subset monitoring is useful in identifying decreasing CD8 T lymphocyte levels that predict short-term prognosis.
Ref: Sabin CA, Mocroft A, Bofill M, Janossy G, Lee CA, Johnson M, Phillips AN. Journal of Infectious Diseases 1998 Oct; 178:1166-1169.
|
As concerns the importance of CD8 T cells in patients with less than 5 CD4 T cells, Sabin et al. report that "While overall there were no clear trends towards a drop or increase in either count, persons who died during the study experienced a rapid drop in both CD8 T lymphocyte and total T lymphocyte levels in the months preceding death." "The last CD8 and total T lymphocyte measurements before death were low (median CD8 cells, 235/mm3; median total cells, 400/mm3)." "The results from the current study emphasise the importance of continued lymphocyte monitoring in persons in whom the CD4 T lymphocytes have become undetectable." "At late stages of HIV infection, CD8 T lymphocytes may be infected with HIV, and a loss of CD8 T cells at this stage may be due to direct killing by the virus. Our results are consistent with this hypothesis, although the finding that the CD8 T lymphocyte count does not rise following treatment with double nucleoside antiretroviral therapy argues that direct virus killing is not the only explanation for a loss of CD8 T cells at late stages of infection."
|
Major surgery seems not to influence HIV disease
progression in haemophilia patients. The influence of major surgery on HIV disease progression and decline in CD4+ cell count was evaluated in 23 seropositive haemophilia patients. 24 HIV-infected patients served as non-operated controls. In addition, 32 age-matched seronegative subjects were included. The follow-up time was up to 5 years. During the course of the study, eight of the operated (35%) and 11 of the non-operated (48%) subjects developed HIV-related symptoms (P=0.267). The relative risk for developing HIV-related symptoms after surgery was 0.60 (95% CI 0.25; 1.48). A significant decline in CD4+ cell counts was observed in both the surgery (4.0 x 10(6)/l/month, 95% CI 2.0; 6.0 x 10(6), P=0.001) and the non-surgery (4.0 x 10(6)/l/month, 95% CI 2.0; 6.0 x 10(6), P=0.004) seropositive subgroup, but no difference between the two subgroups was seen (P=0.793). HIV (6.0 x 10(6)/l/month, 95% CI 2.1; 9.9 x 10(6), P=0.0005) but not surgery (-1.0 x 10(6)/l/ month, 95% CI -3.0; 0.96 x 10(6), P=0.647) was an independent predictor for the decline in CD34+ cell count. No interaction effect was observed between HIV infection and surgery (P=0.361). The annual amount of factor concentrate used for regular replacement therapy did not influence the decline in CD4+ cell count (P=0.492). The researchers conclude that major surgery may be considered in symptom-free HIV-seropositive haemophilia patients, with CD4+ cell counts > or = 0.20 x 10(9)/l under similar premises as for seronegative subjects.
Ref: Astermark J, Lofqvist T, Schulman S, Stigendal L, Lethagen S, Nilsson IM, Berntorp E. Br J Haematol 1998 Oct;103(1):10-4
|
OPPORTUNISTIC ILLNESS
|
Effects of protease inhibitors on the course of CMV retinitis in relation to CD4+ lymphocyte responses in HIV+ patients
Abstract Aim: To gain insight into the course of CMV retinitis (CMVR) in AIDS patients receiving protease inhibitors (PI), and to evaluate whether certain patterns of CD4 response are indicative of the clinical outcome and the risk of recurrence.
Methods:-15 consecutive AIDS patients receiving maintenance therapy for CMVR were included in a prospective observational cohort study at the university hospital between July and October 1996. Patients were evaluated for signs of CMVR activity and intraocular inflammation. CMVR recurrence was defined as the primary clinical endpoint. Follow up was performed until July 1997. No patient was lost to follow up. Clinical outcome was related to CD4+ lymphocyte counts. which were monitored every 6 weeks. Highly active antiretroviral treatment regimen including PI was started at study entry.
Results. All recurrences (n=7) were in patients who failed to have a sustained increase in CD4 counts, whereas CMVR remained inactive during a follow up of 42-52 weeks in those who were able permanently to restore their CD4 values to 100x10(6)/l or more (n=5). The remaining three patients died after 12, 16, and 50 weeks, respectively, without recurrences. All relapses of CMVR were seen after 6-16 weeks, and at CD4 counts well below 100x10(6)/l.
Conclusions. The beneficial effects of PI treatment correlate with the pattern of CD4 response. Sustained increases in CD4 counts achieved in the first 16 weeks of treatment are associated with a prolonged period of CMVR quiescence. Poor initial response is associated with a high risk of CMVR recurrence.
Ref: Van den Horn, G.J., Meenken,C., Danner,S.A., Reiss,P., De Smet,M.D.: Br.J.Ophthalmol., 82 (9):988-990 (1998 Sep)
Eradication of AIDS-Related Disseminated Mycobacterium avium Complex Infection after 12 Months of Antimycobacterial Therapy Combined with Highly Active Antiretroviral Therapy.
To determine if microbiologic cure of AIDS-related disseminated Mycobacterium avium complex (MAC) is possible in patients receiving highly active antiretroviral therapy (HAART), 4 patients with a history of disseminated MAC received >/=12 months of macrolide-based antimycobacterial therapy. All were asymptomatic and had absolute CD4 cell count >100/muL (range, 137-301) and <10,000 copies/mL of human immunodeficiency virus RNA (range, <500-1250). A bone marrow aspirate and peripheral blood were obtained for mycobacterial culture. Follow-up blood cultures were obtained routinely at 4 weeks and every 8 weeks thereafter. All 4 patients had negative bone marrow and blood cultures and then discontinued antimycobacterial therapy. All patients' subsequent cultures remain sterile and all are clinically asymptomatic (range, 8- 13 months follow-up). It appears that disseminated MAC infection can be cured by prolonged antimycobacterial therapy in some persons who experience sustained CD4 lymphocyte increases while receiving HAART.
Ref: Aberg JA, Yajko DM, Jacobson MA. J Infect Dis 1998. Nov;178(5):1446-1449.
|
ON THE WEB
|
Genetic Database for Sexually Transmitted Diseases Goes Online
The STDGEN Relational Database, a database of genetic information on infectious pathogens that cause sexually transmitted disease, is now available online. The database http://www.stdgen.lanl.gov translates gene sequences from infectious agents into their coded gene products and organises that data into functional groups.www.stdgen.lanl.gov Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said researchers can use the new database in their efforts to develop vaccines, microbicides, or therapeutics against STDs. The database currently holds information of Chlamydia trachomatis, Treponema pallidum, and Mycoplasma genitalium; researchers plan to add information of Neisseria gonorrhoea, Ureaplasma urealyticum, and human papillomavirus in the upcoming year.
Comprehensive Aspergillus Website Opens
The Infectious Diseases section of The University of Manchester Department of Medicine has recently launched a new website devoted to the opportunistic pathogen Aspergillus. It contains a section on the treatment of Aspergillosis and patient information translated into several languages. The new website can be found at:
http://www.aspergillus.man.ac.uk
MMWR Recommendations and Reports --- Prevention and Treatment of Tuberculosis Among Patients Infected with Human Immunodeficiency Virus:
Principles of Therapy and Revised Recommendations These guidelines update previous CDC recommendations for treating and preventing active tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV). The most notable changes in these guidelines reflect both the recent advances in the use of antiretroviral therapy and the findings of clinical trials that evaluated new drug regimens for the treatment and prevention of TB among HIV-infected persons. Antiretroviral therapy is discussed in the context of TB treatment only; more detailed information about antiretroviral therapy is published elsewhere. All HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy, because most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies. However, the use of rifampin with protease inhibitors or non- nucleoside reverse transcriptase inhibitors is contraindicated. The report is posted on the CDC Division of TB Elimination Internet website at: http://www.cdc.gov/nchstp/tb and the MMWR website at: http://www.cdc.gov/epo/mmwr/mmwr.html Readers should consult these sources regularly for updates in the guidelines
|
ATP Dr FAX SYMPOSIUM RESISTANCE ASSAYS IN CLINICAL PRACTICE 22nd October 1998, London.
|
The full report will be distributed at the upcoming 4th International Congress on Drug Therapy in HIV Infection, 8 - 12 November 1998 and is also available on request from the ATP office.
OVERVIEW At the beginning of the symposium, Professor Clive Loveday, Virologist, The Royal Free Hospital, presented an overview of genotypic and phenotypic resistance assays. A table is presented detailing comparative characteristics including ease of use, cost and sensitivity limitations (see full report). Professor Loveday also presented the results from the first prospective study (Viradapt Trial, see full report) of a resistance assay.
ASSAYS Seven different assays were presented (described on page 9 with a table on page 10- 11 in full report) followed by a discussion where several issues were raised: _ standardised presentation of assay results needed and should be peer-reviewed _ production capacity and its ability to meet future demands _ accuracy of assays at detecting non clade -B viruses _ systematic quality control needed
CLINICAL PRACTICE This was followed by two presentations examining resistance assays in clinical practice. Dr Ian Williams, HIV Consultant, University College London, pointed out: We now know that resistance testing is predictive of virologic response and that the clinical utility of resistance testing could be for: _ starting treatment _ assessment of poor virologic response _ assessing the cause of virologic rebound _ switching therapy _ post-exposure prophylaxis (test donor) _ to ensure the delivery of clinically effective antiretroviral therapy for the individual patient. Dr Deenan Pillay, Clinical Virologist, Public Health Laboratory, Birmingham, UK noted that there are a number of determinants that influence the interpretation of drug resistance results: _ number and classes of previous drugs used _ resistance to some drugs is more predictive than for others _ varying degrees of adherence _ transmission of resistant viruses Dr Pillay pointed out that ultimately, the two most important questions, are: _ does knowledge of resistance data alter clinical management? _ if so, does this lead to an improved clinical and virologic outcome?
DEFINING THE SITUATION Dr Tom McManus, HIV Consultant, Newham General Hospital, London, and Dr Stephen Ash, HIV Consultant, Ealing Hospital, London, then posed several questions to the participants for open discussion: 1 Is there a need to present a united front to funders? If so, how will this be developed and supported? The discussion centred around the fact that resistance assays are already being implemented in clinical practice: that we must collect data to support their optimal use and clarify when resistance testing should be done. In particular, at what point in infection, during treatment and how often? Which tests are most appropriate to use in different circumstances? 2 If we need more data to support the use of resistance assays, how will that data be generated? How long will it take to generate results that are clinically meaningful in randomised trials or databases? 3 How will we deal with patchwork access to resistance testing and patient migration? To ensure that this does not happen, how will a necessary infrastructure be created? Will local testing results be interpreted differently across the country? 4 Where will the organisation to achieve coherent implementation come from? At present there is little co-ordination between laboratories and clinics on a national level. In the current health purchasing environment, innovation comes more often as a result of pressure rather than from scientific data. This leads to poor co- ordination and unequal access - the loudest voices get heard first. There were strong areas of consensus: _ cost-effectiveness of resistance assays is clear _ resistance tests should be used during pregnancy, in PEP and to build up databases _ routine storage of patient blood samples for later testing should start now _ systematic testing of stored samples from previous clinical trials could provide further validation _ current NHS budgetary systems are limited in that they do not allow for modest spending in one area to be offset by significant savings from another Structures must be identified to: respond quickly and efficiently to scientific developments, identify relevant questions, develop effective strategies, promote the active exchange of ideas and rapidly disseminate information as it emerges. A national strategy for access to resistance assays is needed, simultaneously collecting essential data through a national database - the more treatment centres that participate, the more meaningful the results will be.
SEARCHING FOR SOLUTIONS Dr Charles Boucher, Virologist, University Hospital Utrecht, The Netherlands, and Emilio Ledesma, European AIDS Treatment Group and Fundacion de Informacion Sobre Tratamientos, Spain, looked to the future for solutions and pointed out that the following interest groups need to be involved in the responsible use of resistance assays : _ clinical practice: routine screening to choose appropriate drug combinations _ industry: a duty and interest in developing supporting structures and information _ regulatory authorities: make use of resistance testing in drug registration _ HIV service organisations and funders: shift resources to meet the demands of complicated treatment decision-making. Organisations must develop expertise of the highest level possible and pay special attention to the quality and timeliness of information _ collaborative efforts between companies: need to be co-ordinated by doctors and patients
DISCUSSION OF SOLUTIONS A solution-based discussion then focused on three questions: 1. When should we use resistance testing? _ in pregnancy and for post-exposure prophylaxis _ phenotypic and genotypic assays during primary infection to follow the epidemiology of resistant virus _ still unclear for heavily pre-treated patients _ several prospective trials already do, or will soon confirm, a key role in many aspects of clinical practice _ routine collection and storage of blood samples at critical treatment junctures _ more patients must be tested to gain best information 2. How can we ensure that clinicians receive appropriate training and clinical support and that patients receive clear and meaningful information on resistance testing and what do the results mean? _ a system of advising clinical virologists needs to be established _ expertise from clinical trials and databases should be widely disseminated _ clinical governance is needed to ensure and support consistency of practice 3. Must we, and can we, conduct clinical trials to establish the effectiveness and best use of resistance testing? A national database should be developed to provide information needed to support best use of resistance testing in clinical practice, collecting data on: test results, clinical decisions and virologic, immunologic and clinical outcomes over time. _ genotypic and phenotypic assays should both be performed to understand correlation _ databases should meet international standards to allow cross- talk _ a source of practical co-ordination needs to be identified
TAKING THE SCIENCE FORWARD Looking to the future, Dr John Mellors, Virologist, Pittsburgh University, raised the following issues.. Persistent viral replication despite the presence of HAART therapy is caused by a variety of factors, leading to drug resistance. Resistance assays can measure this in two ways: genotype to provide an early warning of accumulations of mutations and phenotype as a tool to analyse complex resistance with multiple mutations. Supportive evidence for both genotyping and phenotyping exists: _ resistance testing predicts short term response in experienced patients _ more prevalence studies in naive patients needed _ further validation and standardisation necessary Dr Franois Clavel, Virologist, Antiviral Research Laboratory, Bichat Hospital, Paris, provided some insightful views on future developments. In particular, he profiled a bench-top phenotyping kit of the future. This, he suggested, would have to be recombinant, based on a single-cycle replication and that it need not be HIV- based, i.e. other viruses, yeast or bacteria might be used as vectors. He drew attention to the following issues: _ the need for thorough geno-pheno databases for genotype to predict phenotype _ the future of early resistance detection is mixed _ early escape virus is not always resistant virus _ minor virus variants cannot yet be detected Dr Clavel examined the future use of fitness assays, noting most resistance mutations must be disadvantageous, but compensatory mutations can correct some loss of fitness. He also noted that assessing drug metabolism parameters may provide a way to overcome resistance by allowing higher drug concentrations.