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8th European Congress of Clinical Microbiology and Infectious Diseases May 25-28, 1997. Lausanne, Switzerland.
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8th European Congress of Clinical Microbiology and Infectious Diseases
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May 25-28, 1997. Lausanne, Switzerland.
The European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), is the official conference of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). This years conference saw a sizeable number of presentations and abstracts on HIV and AIDS from leading clinicains and researchers in the field.
AIDS Treatment Project provide the following report and selected abstracts from this recent meeting.
Expert opinion still appears divided on the issue of when to start treatment for HIV-infection, There is now, however, an apparently overwhelming consensus that once a decision to treat has been reached, then treatment should be initiated with currently optimal therapies. In virtually all cases this is interpreted as nothing less than combination therapy consisting of 2 nucleoside analogues and a protease inhibitor, if tolerated.
In a session on Tuesday entitled The role of resistance and dynamics of HIV in antiviral therapy Doug Richman outlined the impact that new understanding of the pathogenesis of HIV-disease has on the application of antiretroviral agents. According to Richman ...the parameters for chemotherapeutic intervention are provided by understanding the source of plasma virus, its relationship to loss of immune function, the magnitude of virus replication and the turnover rates of viral pools. Richmans primary concern was in highlighting the rates of generation of genetic variants, the pre-existence of resistant mutants and the factors needed to suppress the emergence of drug resistance which should act as a guide to antiviral strategies.
As a spokesman for the treat hard approach Richman stated that ...treating with anything less than currently optimal therapies is an invitation to resistance. Drug resistance then leads to therapeutic failure and the patient becoming increasingly refractory to future treatment. If you are going to treat, you must treat hard urged Richman, using 2 nucleoside analogues and a potent protease inhibitor.
Two current treatment strategies were defined:
Vs.
Richman also attacked the practise of including non-nucleoside reverse transcriptase inhibitors (NNRTIs) and/or 3TC (lamivudine) in any combination which is not designed to completely suppress HIV replication -- i.e. double nucleoside analogue (NA) combinations or combinations of one NA and one NNRTI. He described both 3TC and NNRTIs as potent agents with the drawback of high level resistance through the rapid accumulation of a single mutation. The key to the use of these drugs is seen to be in preventing emergence of resistance by inclusion in a maximally suppressive regimen, thereby preserving their potency of action by preventing resistance.
Stressing the impact of current decisions on future treatment strategies Richman warned that ...using zidovudine and 3TC alone, and not achieving complete suppression will have life-long consequences -- no future use of 3TC in a potent 100% suppressive therapy.
These sentiments were similarly expressed by Anthony Pinching of St Bartholomews Hospital, London, in his state-of-the-art lecture Which drugs for which patients?
Pinching outlined his view of best current treatment strategy using philosophical frameworks rather than guidelines or cook-book medicine. The presentation outlined the PACT framework for antiretroviral therapy which was reproduced in ATPs Doctor Fax Issue 19. Pinchings conference lecture illustrated the same qualities of the PACT framework that have been welcomed by patients and treatment advocates as providing a flexible and sensitive approach to the antiviral therapy of HIV-disease.
There is, Pinching stated ...an inherent plausibility to hitting early and hard. He also endorsed the use of viral load measures using PCR along with CD4 cell response as ...good surrogate markers used to inform treatment strategies.
Echoing Doug Richman in the careful choice of agents in any initial combination Pinchings message was to invest wisely and that ...any viral turnover suggests a change of multiple agents.
Refs: Richman, D.D. The Role of Resistance and Dynamics of HIV in Antiviral Therapy.
[S0092}8th European Congress of Clinical Microbiology and Infectious Diseases 1997.
Pinching, A. Which Drugs for Which Patients? [S0091] 8th European Congress of Clinical
Microbiology and Infectious Diseases 1997.
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Although there may be some dispute amongst researchers and clinicians over the choice
of agents employed as antiretrovirals, the consensus emerging seems to be that, if tolerated, drug combinations with the best ability to reduce viral load to undetectable levels should be employed. We now know
that a combination of two nucleoside analogues (NAs) such as ZDV/ddI, in a treatment naive population, can lead to viral load below
the level of detection in around 30-40% of patients. Similarly combining two NAs with an NNRTI such as nevirapine has led to 70% of trial participants achieving
undetectable. With the use of two NAs and a protease inhibitor as many as 80-90% of patients may achieve this goal. Perhaps all these options are viable, but only if viral load testing is available at, say, six weeks to check that virological control (reduction of viral load below detectable) has been achieved. In the case of regimens including 3TC incomplete suppression and the emergence of resistance is likely to influence subsequent response to ddC, ddI and (worryingly) the new Glaxo Wellcome nucleoside analogue 1592U89 (abacavir). Similarly incomplete suppression with an NNRTI containing regimen may limit future response to newer NNRTIs such as DMP-266. Control may be achieved, and maintained with two drugs, if not consideration of the inclusion of a third agent must be made promptly in a second attempt to drive viral load below detectable, thereby delaying the emergence of drug resistant virus. Many physicians have concluded that there may be little advantage (other than economic) in this approach and have adopted the hit hard strategy with all patients, using the drug combination which has been shown to reduce viral load to below detection most reliably (ie. 2NAs + PI). Ultimately the best or optimal therapy has to be the one which both the patient can take and that results in a viral load below detectable levels. This appears to be the only mechanism, at present, which will ensure some durability of the drugs being used, and the preservation of future treatment options by forestalling resistance. The key to such a treatment strategy is the availability of viral load testing. Evidence of continued viral replication in the presence of drug therapy should be considered a matter of urgency, and if further antiretroviral treatment options exist, they should be explored. With leading treatment centres having six week waiting times for viral load test results any such strategy for preventing resistance, extending the useful life of antiretrovirals and keeping future treatment options open becomes a nonsense. If patients engage in antiretroviral treatment, viral load monitoring should be frequent and the results available in real time. It is ATPs considered opinion that continued viral replication in the presence of these drugs, even for six weeks, may have the potential to seriously limit future antiretroviral efficacy. |
| SELECTED ABSTRACTS
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Several therapeutic trials using combined therapy (2 reverse transcriptase inhibitors (RTI) or 2 RTI in combination with antiprotease), have induced in a majority of patients enrolled, a drop of viraemia to undetectable levels (less than 200 HIV-1 RNA copies/ml). By using a modified assay for viraemia with a detection limit of around 10 copies/ml, we have shown that a number of patients had viraemia levels between 10 and 200 copies/ml, 6 to 15 months after initiation of treatment. However, lymphoid organs are the main site of viral storage and replication. Thus, analysis of lymph node biopsies might provide more in depth information on treatment efficacy.
In this context, preliminary data in patients with viraemia lower than 10 HIV RNA copies/ml shows an absence of viral deposits and no evidence of viral replication in lymph nodes. In contrast, patients with residual low viraemia levels have incomplete clearance of viral deposits and low viral replication in lymph nodes.
Concomitant analysis of viral load in blood and lymph nodes might help to evaluate therapeutic efficacy and to define guidelines for treatment (interruption of treatment, change in treatment or introduction of a simplified long-term maintenance therapy).
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The issue of undetectable is obviously changing with the availability of tests with increased sensitivity.
Although low levels of viral turnover (between 10 and 200 copies/ml) may not allow for disease
progression, could these levels still be high enough to allow mutation and genetic escape from antiviral control? Eradication
, if possible, may only be on offer to the select few (recent seroconverters and those who can achieve viral loads of close to zero
copies). Durability of antiviral action will then be the key to reaching a normal lifespan with HIV-infection. How low must
viral load be maintained in order to forestall drug resistance? In an accompanying presentation Luc Perrin stated that in the case of chronic infection (the vast majority of cases) not one patient has managed to maintain a continuous period of aviraemia when serially tested with PCR -- all have peaks and troughs |
| Severity of seroconversion has previously been associated with risk of progression. Most UK clinics are now offering triple combination therapy to recent seroconverters. |
| Clearly, tolerability and compliance are crucial issues affecting the outcome of this double protease inhibitor combination. In patients with advanced disease and substantial prior therapy it appears that replicating HIV can rapidly accumulate multiple mutations and overcome substantial genetic barriers. In less advanced patients the combination of saq and rit has reduced viral load below 200 copies/ml in around 80% of patients at week 24. |
CD4 and HIV-RNA (QuantiplexÆ HIV-RNA 2.0; assay detection limit, 500 copies/ml) determinations were carried out at Weeks 0, 4, 8, 16, 24.
| (n pts) | Baseline | W4 | W8 | W16 |
| Mean CD4 | 330 (52) | 432 (50) | 429 (43) | 439 (28) |
| Mean log RNA | 4.48 (50) | 2.98 (48) | 2.94 (47) | 3.06 (34) |
| RNA/baseline | - | 1.50 (48) | 1.55 (47) | 1.42 (34) |
| % undetectable | 0 (50) | 66.7 (48) | 72.3 (47) | 76.5 (34) |
6 pts discontinued the study due to poor compliance (2 pts), own request (1 pt) and
adverse events (3 pts).
Centre Hospitalier Universitaire de Montpellier, France
Didanosine was administered at a dosage of 300 mg (200 mg if weight <60 kg) once a day and zidovudine at a dosage of 250 mg (300 mg if weight >60 kg) twice a day. CD4 and HIV-RNA (NASBA HIV-1 QT assay, detection limit: 400 copies/ml) determinations were carried out at Weeks 0, 8, 24.
The CD4+ count at entry was 278 181 cells/ l. The mean increase was 102 cells/ l at W8 and 156 cells/ l at W24. Five patients discontinued before W24 (poor compliance, 3 pts; adverse events, 2 pts).
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Once-daily administration of didanosine appears to be as effective as twice-daily
administration in zidovudine/didanosine combination therapy. Once daily ddI is now used with increasing frequency by clinicians. Although there is no comparator arm in this study the antiviral activity is consistent with that achieved in previous studies using bid dosing. Other studies are planned to allow Bristol-Myers Squibb licensing for once daily use. |
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OTHER ITEMS
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Dr. Philippe Vanhems of Hotel-Dieu de Montreal in Quebec, Canada and colleagues investigated 218 patients to ascertain the frequency and duration of the symptoms of documented primary HIV-1 infection. The study subjects included men and women with different risk factors to reflect the diversity that physicians may actually see in a clinical setting.
Dr. Vanhem's team found that symptoms persisted for a median of 25.1 days, and observed no differences in the length of the acute HIV-1 infection by age, sex or risk group. The most common symptoms, in order of frequency, were fever, lethargy, cutaneous rash, myalgia and headache. More than 50% of the subjects developed these symptoms.
However, they also noted that "...15.6% of patients presented with a typical mononucleosis-like illness (MLI) defined as fever, pharyngitis or sore throat, and cervical adenopathy, and 10% had no features of MLI." Twenty patients developed a meningitis-like syndrome.
Based on these results, they conclude that patients with acute HIV-1 infection may present with a wide variety of symptoms, and less than 20% have classical mononucleosis-like illness. "A febrile syndrome, especially one associated with gastrointestinal or mucocutaneous features, occurring in a person at risk of HIV infection should alert physicians to the possibility of HIV-1 seroconversion."
Ref: Clin Infect Dis 1997;24:965-970.
Source: Aegis
Ref: JOURNAL: AIDS [Fast Track] VOLUME: 11
Source: Sci.med.aids
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Studies such as Abbot 247 of ritonavir have underlined the potential for intervention
with protease inhibitors to improve outcome in persons with very advanced disease. With better use of new agents (eg. switching
NAs and adding a PI) substantial improvements, durable over more than 1 year, in CD4,
clinical status and quality of life may be observed. Much of the data from the above study reflects outcome prior to widespread
use of protease inhibitors.
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Ref: Nature Medicine (05/97) Vol. 3, No. 5, P. 549; Mullins, James; Walker, Bruce;
Wolinksky, Steve; et al.
Source: AIDS Daily Summaries
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It is not surprising that viral load alone does not determine risk. However, whilst
this study and 076 found no threshold, higher viral load did increase risk of transmission. Antiviral intervention in pregnancy
usually begins at week 14 or beyond. Infection of the foetus in utero (estimated in up to a third of cases) has been reported
prior to week 14. These studies may not, therefore, fully assess the benefit, of reducing viral load with treatment, on progression.
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Researchers from Johns Hopkins University and the National Institutes of Health found that HIV-1's ability to produce latent infection of CD4 T cells could sustain the virus, even when a patient is being treated with antiretroviral therapy. They report that during the asymptomatic phase of infection, there is a very low total body load of latently infected resting CD4 T cells with replication-competent integrated provirus. The most common form of HIV-1 DNA in resting and activated CD4 cells is a full-length, linear, unintegrated form that is not replication competent. According to the researchers, viral infection continues even though integrated HIV-1 DNA is present in the lymphoid tissues in only a minuscule amount of the susceptible populations at any given time.
Ref: Nature (08/05/97) Vol. 387, No. 6629, P. 183; Chun, Tae-Wook; Carruth, Lucy;
Finzi, Diana; et al.
Source: AIDS Daily Summaries
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OTHER ITEMS
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In a comment on this item it was incorrectly implied that Roche had failed to submit a similar application to the EMEA in Europe. In fact the submissions for the saquinavir soft-gel capsule were made simultaneously in Europe and the US.
ATP would like to apologise to Roche for implying a delay on their part over European licensing.
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Even though submissions may take place simultaneously to both the FDA in the US and
the EMEA in Europe, it is still the case that much needed new treatments for HIV-infection normally appear in US pharmacies at
least six-months before a licensing decision is reached in Europe. With the new formulation of saquinavir, ATP understands that
the EMEA will not treat the application for licensing with priority - hence it is likely that this drug will reach patients in
the US sometime in the third quarter of this year, but European patients are likely to have to wait until sometime in the second
quarter of 1998! This situation in Europe is unacceptable to people with AIDS and their physicians and must be addressed as a matter of urgency by the European Medicines Evaluation Agency. |