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TREATMENT ALERTS
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Merck & Co. is adding a warning to the labelling of their drug indinavir (Crixivan)
regarding 20 cases of haemolytic anaemia reported among a total of 140,000 people using indinavir -- an incidence of 1 in 7,000.
Eleven cases were reported in the USA, four in France, and one each in the UK, Spain, Switzerland, Canada, and Australia.
A variety of drugs can cause haemolytic anaemia, which is defined as a premature destruction
of red blood cells. The most common symptom is fatigue, but jaundice and reddish-brown urine have also been reported.
Since this condition may progress rapidly and become quite severe, it must be recognised and treated quickly. Mild cases may
not require any treatment other than stopping the drug, moderate cases may be treated with the corticosteroid prednisone, and
severe cases may require blood transfusions or more complex treatment.
Merck notes that most cases of haemolytic anaemia occurred within 43 days of starting
indinavir, and that 11 of the 20 patients had been taking other drugs known to cause this form of anaemia (for example, Septrin
or dapsone). However, all 11 had been using these other drugs for a long time without developing this condition. Four cases
were considered life-threatening, and one patient died, probably as a result of this side effect. Five cases resolved after stopping
indinavir, and two of these patients were later able to restart indinavir safely.
Indinavir-related haemolytic anaemia is a rare condition. Nonetheless, patients and
doctors should be aware of the connection and remain alert to signs of unusual fatigue or changes in lab tests of red blood cells.
Source: CATIE News
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Haemolytic anaemia has previously been reported as an adverse event with the PCP prophylactic
dapsone, particularly in some ethnic groups in which G6PD deficiency is common. Haemolytic anaemia has also been reported
in isolated cases with other protease inhibitors. It is not yet known if this may be an across-class effect. |
Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing
regimens for patients with HIV-1 infection: the CAESAR trial
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This study confirms the clinical benefits of 3TC combinations in patients who were mostly (86%) ZDV experienced. Benefit for adding 3TC was similar in patients who were on ZDV alone, ZDV/ddC or ZDV/ddI, confirming
the view that 3TC remains active after treatment with these Delta combinations. No studies with the reverse sequencing (ie. ddC or ddI after initial
3TC) have been reported. The CAESAR study also did not directly compare the benefits of the Delta combinations with ZDV/3TC as
initial therapy. Further data is therefore needed to assess the best role for 3TC. |
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CURRENT OPINION
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The CAESAR trial reported in The Lancet evaluated the impact of adding lamivudine
(a nucleoside analogue reverse transcriptase inhibitor, NRTI) or lamivudine plus loviride (a non-nucleoside reverse-transcriptase
inhibitor, NNRTI) to zidovudine-containing antiretroviral regimens. The results of the study are clear - giving lamivudine to
patients already on NRTI-based agents can significantly reduce progression to AIDS and death. However, as the authors themselves
point out, the combination of zidovudine and lamivudine alone cannot achieve durable suppression of HIV replication in most treated
patients. Thus, although it was important to evaluate that strategy at the time that the CAESAR trial was started, the regimen
used must now be regarded as suboptimum.
The HIV reverse-transcriptase (RT) is an "error-prone" enzyme, which makes frequent
mistakes while copying the viral RNA into DNA during an essential step in the virus life-cycle. The numerous rounds of HIV replication
taking place every day in infected persons provide the opportunity to generate large numbers of variant viruses, including
those with diminished sensitivity to antiretroviral drugs. The great genetic diversity of the resident population of HIV means
that viruses resistant to one (or several) antiretroviral drugs are likely to be present in infected individuals before antiretroviral
therapy is started. Once drug therapy is begun, that population of drug-resistant viruses can rapidly predominate. Drugs
such as lamivudine and the NNRTIs (such as nevirapine, delavirdine, and loviride) select for drug-resistant variants that harbour
single-nucleotide changes in the HIV RT gene that confer hundredfold to thousandfold reductions in drug susceptibility. Thus,
although these agents may be potent inhibitors of HIV replication, their antiretroviral activity when used alone or in combination
with one other anti-HIV drug is largely reversed within a few weeks because of the rapid proliferation of drug-resistant variants.
Worse, many of the existing antiretroviral drugs select for the proliferation of HIV variants that are resistant to drugs
with which the patient has not been treated (cross-resistance). Since effective antiretroviral drugs are limited in number and
mechanism of action, their use in ways that encourage multidrug resistance greatly compromises a patient's options for future
effective therapy.
The CAESAR study is but one of several studies that show that the degree of the clinical
benefit obtained by the addition of even a potent antiviral drug to ongoing NRTI monotherapy or combination therapy decreases
as the duration and variety of past antiviral drug exposure increases. Many HIV-infected individuals who receive regimens like
that used in the CAESAR study, and recommended recently as initial therapy by the British HIV Association, are now unable to
obtain lasting benefit from the addition of potent protease inhibitors, because once resistance develops to the NRTI components
of the most effective combination regimens, the protease inhibitor essentially behaves as monotherapy - fertile territory for the
selection of HIV variants resistant to several (and perhaps all) protease inhibitors. With these considerations in mind, it has
been argued that only drug regimens that are expected to suppress HIV replication to undetectable levels should be studied in
clinical trials or adopted in clinical practice.
Several important principles can be used to guide the choice of antiretroviral therapy.
Thus at present the most effective and reliable way of preventing the emergence of
drug-resistant viruses and of achieving maximum protection from HIV-induced immune-system damage is to use two NRTIs (eg, zidovudine
and lamivudine) in combination with a potent, bioavailable protease inhibitor (eg, indinavir, ritonavir, or nelfinavir),
to suppress HIV replication to undetectable levels (as assessed by plasma HIV RNA). As predicted, this approach works best in antiretroviral-naive
patients. For those who have been exposed to NRTI and who have detectable levels of plasma HIV RNA, the addition
of a protease inhibitor should be accompanied by a change of at least one other component of the treatment regimen, keeping
in mind the patient's previous antiretroviral treatment.
With the advent of life-saving therapies for HIV infection, all practitioners caring
for HIV-infected persons must strive to keep abreast of rapidly evolving advances in HIV therapeutics to ensure that new agents
are used in the safest and most effective ways. Unfortunately, the rate of progress has recently outstripped the pace with which
new findings are published. Certainly, CAESAR and ACTG 1757 were important studies, but their results now serve historical rather
than current needs. Even so, investigators and pharmaceutical companies must be encouraged to publish their findings in full
as soon as they are sure of the validity of the results, so that practitioners have a rational basis on which to use new antiretroviral
drugs.
Mark Feinberg
Office of AIDS Research, National Institutes of Health, Bethesda MD 20892, USA
Source: The Lancet, Vol 349, May 17, 1997. 1408-1409.
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OPPORTUNISTIC ILLNESS
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HIV-1-infected patients whose CD4 counts have responded to antiretroviral therapy
should continue taking prophylactic drugs against opportunistic infections until more is known about the safety of halting theses
treatments, said experts at a symposium on HIV-1-related pulmonary disease (May 19). Prophylaxis against Mycobacterium avium-intracellulare
complex (MAC) in patients with CD4 counts less than 50 cells/microL is now "the standard of care", said Richard Chaisson
(Baltimore, MD, USA). Prophylaxis should be initiated with either azithromycin or clarithromycin. Rifabutin should be used
as a second-line drug. Prophylaxis should be continued even if patients respond to antiretroviral therapy, he added. Henry Masur
(Bethesda, MD, USA) warned that Pneumocystis carinii pneumonia does occur in patients with CD4 counts much higher than 200 cells/microL,
the level at which prophylaxis is generally instituted. Again, prophylaxis should be continued in patients whose CD4
counts rise with antiretroviral therapy. He added that co-trimoxazole seems to be so much more effective than other drugs in preventing
P carinii pneumonia, that it may be advisable to put patients on doses lower than the standard daily double-strength tablet
in the hope the drug will be better tolerated.
Ref: Lancet 349:1607 (May 31, 1997).
American Thoracic Society & American Lung Association Meeting, 16-21 May, San Francisco,
USA.
| Continuing PCP prophylaxis in CD4 responders to antiretroviral therapy is standard practice in the UK. Anecdotally, some clinics are stopping combination therapy for MAC patients after 6 months in CD4 responders (rises above 200 cells/l) and using azithromycin 1250mg once weekly as secondary prophylaxis. |
Researchers from the New York University Medical Center recently examined the safety
and tolerability of aerosolised interferon-(gamma) in patients with multidrug-resistant tuberculosis. Five patients with smears
and cultures positive for the disease received the drug for one month. The researchers concluded that interferon-(gamma) was
well-tolerated by all patients and produced only minor adverse effects, including muscle aches and cough. Moreover, the drug
helped all five patients to either gain weight or stop losing weight and reduced the size of cavitary lesions produced by the tuberculosis.
The authors concluded that aerosol interferon (gamma) is "a well-tolerated treatment that may be useful as adjunctive
therapy in patients with MDR-TB who are otherwise not responding well to therapy."
Ref: Lancet (24/05/97) Vol. 349, No. 9064, P. 1513.
Thalidomide effectively heals severe mouth and throat ulcers in people with HIV infection,
according to a study supported by the National Institute of Allergy and Infectious Diseases (NIAID) and reported in the
May 22, 1997, issue of The New England Journal of Medicine.
"For the many patients with HIV infection who suffer from these ulcers, eating can
be excruciatingly painful, which exacerbates wasting and debilitation," says Division of AIDS Director Jack Y. Killen, M.D. "Thalidomide
is the first treatment shown in a scientific study to heal these ulcers, but the course should be carefully monitored
and limited in its duration because of the drugs potential toxicity."
The ulcers of 55 percent of the patients receiving four weeks of thalidomide healed
completely, compared to healing in only 7 percent of the patients receiving placebo. Almost all (90 percent) of those receiving
thalidomide had at least partial healing.
The AIDS Clinical Trials Group (ACTG), a network of clinical trial sites supported
by NIAID, conducted this study, called ACTG 251. Baseline and weekly health evaluations of study volunteers included a quality-of-life
questionnaire to assess pain and discomfort during eating. Results from these questionnaires showed that the thalidomide
group improved much more than the placebo group in regaining comfort while eating.
"Thalidomide appears to have great potential as a therapy for HIV-infected patients
who have severe oral aphthous ulcers," says Lawrence Fox, M.D., Ph.D., one of two NIAID authors, "but only when administered by
a physician who is vigilant for the possible serious side effects, including irreversible, painful peripheral nerve damage, rash
and birth defects.
Patients experienced only minimal adverse effects while they were taking thalidomide.
Seven patients reported drowsiness and seven had rashes. The authors caution, however, that those patients who received thalidomide
showed a small, but statistically significant increase in HIV ribonucleic acid (RNA) blood levels from the baseline through
the fourth week of the study as compared to patients receiving placebo. "There is not sufficient information, however, to judge
whether this increase is of any clinical significance," says study director Jeffrey M. Jacobson, M.D., of the Departments of
Medicine at both Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, New York.
A second reason for caution, according to the study results, is that patients taking
thalidomide had elevated plasma levels of tumour necrosis factor (TNF)-alpha, a substance released from phagocytes and from some
T cells during the immune response and known to provoke HIV replication and expression from infected cells. This was unanticipated
because earlier studies had reported that thalidomide inhibited production of TNF-alpha. These patients also showed increased
soluble TNF-alpha receptor levels, a phenomenon shown to be associated with clinical progression of HIV disease.
Physicians at 19 sites conducted the double-blind, randomised, placebo-controlled
study. Of 57 volunteers, 29 received thalidomide. The remaining patients received placebo, but were offered open-label thalidomide
at the endpoint of the study. All patients in the study were HIV-positive and had oral or throat ulcers for at least two weeks
before the start of the study.
At each of the study sites, physicians evaluated patients in initial screenings, in
baseline physical examinations, and then weekly throughout the study. Because of thalidomides well-known ability to cause severe birth defects, every precaution was taken to
prevent pregnancy, and pregnancy tests were given weekly to women of childbearing age. Each baseline and weekly evaluation included
an assessment of nerve function, (peripheral sensory nerve disorders are a known complication of longer-term thalidomide treatment),
laboratory analyses of blood cells, serum chemistries and serum thalidomide levels, and evaluation of liver and kidney
function.
Ref: Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey J, Jackson JB, Fox L,
Chernoff M, Wu AW, MacPhail LA, Vasquez GJ, Wohl DA. Thalidomide for the treatment of oral aphthous ulcers in patients with human
immunodeficiency virus infection. New Engl J Med 1997;336:1487-93.
Source: NIAID
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The use of thalidomide for HIV-associated apthous ulcers was pioneered by Dr Mike
Youle at the Chelsea & Westminster, London in the late 1980s and has been widely adopted in the UK since. Thalidomide 50-100 mg nocte is effective
therapy with side-effects including sedation and, with chronic use, peripheral neuropathy. |
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CONFERENCE NEWS
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HIV still a formidable foe, European AIDS conference reveals
Interesting new data was reported recently in Stockholm at the 2nd European Conference
on Experimental AIDS Research. While some reports confirm the effectiveness of combination therapy for reducing viral load,
others reveal just how far from won the battle against HIV is.
Dr. Jean-Claude Schmit of the Centre hospitalier de Luxembourg reported on the emergence
of HIV strains resistant to several nucleoside analogues, including AZT, ddI, ddC, d4T and to a lesser degree, 3TC. For a
growing number of patients in Europe, the appearance of these resistant strains is troubling because it limits the number of treatment
options at their disposal. Fortunately, however, the combination of two protease inhibitors seems, according to Dr. Schmit,
to provide a hopeful alternative in these cases.
German researcher Dr. Hans-Jurgen Stellbrink reported a "profound" suppression of
HIV replication in both plasma and lymphoid tissue after three months of antiretroviral treatment combining AZT, ddC and saquinavir.
In fact, this combination appeared to inhibit viral production completely in lymphoid tissue. However, in ten subjects who
stopped treatment, plasma levels of virus quickly returned to their pre-treatment values, thereby shedding doubt on the possibility
of eventually eradicating the virus from infected patients. According to Stellbrink, the successful management of HIV in future
will require combining antiretroviral therapy with effective means of rebuilding the immune system.
In another study, Dr. Hans Nitschko of Munich found that viral production in HIV-1-infected
cells treated with saquinavir dropped significantly within a few weeks of treatment. However, once the drug was removed,
normally functioning viral particles rapidly reappeared, "...even after more than two years of protease inhibitor treatment."
Source: CATIE News.
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In the absence of evidence of eradication, the chronic suppressive model of care remains
the only prudent approach. The BHIVA guidelines recommend keeping HIV levels as low as possible for as long as possible.
What is less clear, however, is the current best strategy for achieving this goal and the sequence in which currently available
agents might be most usefully employed. The recently released draft US guidelines recommend nothing less than protease inhibitor
containing triple combinations as initial therapy for any HIV-infected person considering treatment. This, along with the results
of study SV14604 which shows a clear clinical superiority of such combinations over double nucleosides as initial therapy, will
increase expectations that triple combination therapy including a PI will be the minimum standard of care expected by HIV-infected
persons embarking on antiretroviral therapy. Full details of the new US guidelines and the results of the pivotal SV14604 study will be given in the next issue of AIDS Treatment Projects Doctor Fax. |
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VIRAL LOAD UPDATE
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Amplicor HIV-1 MonitorTM kit now has improved amplification efficiency to HIV-1 group M subtypes. Previously
these clades were not amplified as efficiently by the Roche test, but will now be amplified to the same levels as the B, C and
D subtypes. This has been achieved through the addition of extra gag
primer pairs.
Roche have also developed an ultra sensitive protocol to enable accurate quantitation of virus to 50 or fewer copies/ml. In this
protocol, virus particles are concentrated from 500 l of plasma by ultracentrifugation (24000g) providing a theoretical 10-fold increase
in sensitivity. Full details of this new protocol will be provided to all laboratories using the Amplicor HIV-1 MonitorTM
assay.
Source: Roche
In addition to the hospitals where this assay is available mentioned in ATPs Doctor Fax 21 this test is also now being used at St Thomas Hospital, London and Bristol Royal Infirmary.
The amended list of hospitals carrying out bDNA viral load testing is:
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NOTICE OF MEETINGS
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ISSUE 26 of AIDS Treatment Projects Doctor Fax will include details of the draft new
US guidelines on antiretroviral therapy as well as results from SV14604, the first clinical endpoint study to show clear superiority
of a protease inhibitor containing triple combination over double nucleoside analogues as initial therapy
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PROTEASE INHIBITOR TREATMENT ALERT
DIABETES AND HYPERGLYCAEMIA IN PATIENTS RECEIVING PROTEASE INHIBITORS