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STANDARDS OF CARE
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Satellite Symposium - 10/07/96 Vancouver
| A number of multidrug regimens have demonstrated reductions in viral load to levels below detectability of available tests in persons with primary or recent HIV infection. These studies have not included comparator arms so the magnitude of effect is difficult to assess. Seroconversion studies in Europe, Australia and the U.S. estimate that 15-25% of persons acquiring HIV in urban areas are infected with a zidovudine resistant strain. |
| Nucleoside analogues which require intracellular activation may not represent ideal drugs for PEP due to delayed onset of action unlike protease inhibitors and NNRTIs which are active in administered form. As the source of exposure may be identified in healthcare workers, choice of PEP could be individualised based on the antiretroviral experience of the source patient. |
| Studies of combination therapies for vertical transmission are ongoing (see abstract Tu. 07). UK advice is to offer HIV testing to all pregnant women, but the interpretation of this policy differs from district to district. Under some authorities perceived at-risk mothers are the only ones to be offered testing. |
| How effectively is primary infection identified in the UK? Detection is thought to
be improving, but poor provision of history of exposure and lack of awareness amongst G.P.s may be limiting factors. Suspected seroconversion patients are generally best managed
by specialist centres with access to PCR testing, counselling services and research networks.
The Kobler Centre is conducting ongoing research into the effectiveness of prompt, early treatment of newly infected people with a triple combination of antiretroviral drugs. Referrals of patients who may have
become infected during the last three months may be made to: Dr Mike Youle on 0181-746-5594. A targeted program of both physician and patient education in the U.K. may help in the identification of primary infection. |
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ANTIRETROVIRALS
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"There is no excuse for giving anything less to an HIV-positive patient than three
drugs. And in some cases more drugs may be appropriate."
That blunt advice was offered by Joep M.A. Lange, MD, of the University of Amsterdam,
a clinical investigator who is used to provoking his colleagues with unvarnished analyses of treatment data. The last time Lange
riled some of his more complacent confreres, at a 1994 European AIDS congress in Milan, he insisted that antiretroviral monotherapy
was a doomed strategy, just as monotherapy for tuberculosis had been. A year and a half later, the results of ACTG 175
and the Delta trial erased nearly all resistance to Lange's arguments.
Speaking in Vancouver at two consecutive industry-sponsored symposia on the first
day of the XI International Conference on AIDS, Lange spelled out what he thinks AIDS clinicians should be doing now, if they can
prescribe the eight antiretrovirals available in Europe or the nine being marketed in the United States.
Management of a patient with newly diagnosed HIV infection should begin with measures
of HIV RNA in plasma (viral load) and CD4+ lymphocyte count. Clinicians who have the means to assess drug resistance to antiretrovirals
should do so if they begin caring for individuals who have already been treated by other physicians. Lange said most
Dutch clinicians now believe therapy should begin when the CD4+ lymphocyte count falls below 500 cells/mm3, or when viral load
climbs above 10,000 copies/mL, or when a person has symptomatic HIV disease. Lange contended, though, that the 10,000-copy level
is arbitrary and that viral load "start signals" will continue to decline as more experience accumulates.
Therapy should begin with at least two nucleoside reverse transcriptase inhibitors
and one protease inhibitor, according to Lange. A protease inhibitor should not simply be added to an existing nucleoside regimen.
The choice of an appropriate combination can be guided by several principles (see table). Because virus secluded in the central
nervous system must be attacked, zidovudine (ZDV) or stavudine (d4T), which achieve relatively high CNS levels, should be one
of the starting nucleosides. The aim of initial therapy is to reduce viral load below the assay's limit of detection. If that
goal is not achieved within weeks, Lange said, add a fourth drug to the regimen.
| Joep Langes approach is fast appearing standard rather than aggressive. Compliance with medication is now recognised as being essential to successful long term control of HIV replication. Suppression of viral load to below detection will delay, and possibly prevent, the appearance of resistance. It is not known, however, if persistent viral replication outside the lymphoid compartment will allow resistance to arise. |
In research presented at the 11th International Conference on AIDS (abstracts: LB.B.6046,
We.B.3126, Th.B.4112), economic modelling based on outcomes data and medical care costs in both the United States and United
Kingdom demonstrates that Abbott Laboratories' ritonavir therapy improves outcomes for patients with advanced AIDS and may
thus reduce the annual cost of care.
Investigators also presented research suggesting that clinical benefits demonstrated
with the addition of ritonavir to current antiretroviral therapy correspond with patients' own perceptions of health-related
quality of life.
The research, involving a total of 1,090 patients in North America and the United
Kingdom, modelled the cost of adding ritonavir to existing antiretroviral therapy for patients with advanced HIV infection (Abbott
study 247).
Based on established treatment patterns and cost-of-care data for each country, the
model showed that adding ritonavir to patients' regimens would save an estimated $6,382 in medical costs per patient per year
in the U.S. -- largely in treatment costs associated with new opportunistic infections that would be avoided through the use of
ritonavir. Similarly, in the U.K., the study showed that adding ritonavir to current therapy would save an estimated 5,008 per patient per year. These cost savings results exclude the cost of other
antiretroviral therapies.
These findings were supported by comparing the model's predicted cost savings to actual
costs of medical treatment for the same study population. (Actual costs were defined as prospectively-collected resource costs.)
The results of this analysis demonstrate that patients with advanced HIV infection who receive ritonavir in addition to
their current antiretroviral therapy would be expected to have annual treatment costs for new opportunistic infections that are
substantially less than those for patients treated with usual care. Thus, in patients with advanced HIV infection, ritonavir provides
a survival benefit as demonstrated in previously reported studies, and may provide net cost savings to health plans.
"These results provide compelling evidence to both patients and payers of the importance
of the role of ritonavir in the treatment of HIV infection. We have demonstrated that adding ritonavir to current therapy
improves clinical outcomes in patients with advanced HIV disease. We now know that, in so doing, it also potentially reduces
long-term treatment costs," said Donald Conway, M.D., director of epidemiology and outcomes research at Abbott Laboratories.
Additionally, data presented suggest that the clinical benefits demonstrated with
ritonavir therapy correlate with improvements in patients' health-related quality of life.
During the trial, health-related quality of life was assessed with the Medical Outcomes
Study (MOS) HIV Health Survey, an instrument which has become the standard for evaluating quality of life and medical outcomes
in AIDS clinical trials. This survey was administered at baseline and then at every three months. The ritonavir treated group
showed improvements from baseline in measures of health perceptions, role function, health distress and cognitive function compared
with the usual care group. Patients also were evaluated with a second scale, the EuroQol, a widely-used tool for assessing
quality of life in clinical trials. The EuroQol was administered at every patient visit.
The reported quality of life of patients on usual care as measured by EuroQol showed
a gradual decline over time as expected due to the normal disease progression in this population. By 32 weeks, the scores for
patients on usual care declined from baseline by an average of 2.5 units. By contrast, patients on ritonavir reported a decline
in health-related quality of life during the first two weeks (related to starting side-effects); but by eight weeks of treatment,
the ritonavir group had improved from baseline. By 32 weeks, the ritonavir group reported an average 4.4 unit increase from
baseline in health-related quality of life.
We are encouraged that this state-of-the-art Measurement tool has demonstrated that
patients' perceptions of their functioning and well being are associated with the clinical benefits of ritonavir. As the survival
of patients with HIV disease is extended through treatments such as ritonavir, impact on quality of life and cost-effective
management of these patients becomes more important," said Dennis Revicki, Ph.D. (MEDTAP International, Arlington, Virginia, and
the University of North Carolina-Chapel Hill), a principal investigator in the study.
Source: PR Newswire, 810 Seventh Avenue, New York, NY 10019
| In advanced HIV disease all indications are that QOL and cost are likely to be affected similarly by the addition of any protease inhibitor, not just ritonavir. |
A study to determine the effect of the anti-HIV therapy Epivir(TM),(lamivudine; 3TC) on survival, delay in disease progression or both, has been stopped
after an interim analysis of the data showed a 54 percent reduction in the rate of HIV disease progression, or death, for
HIV patients who had Epivir in their treatment regimen, compared to placebo. The endpoint event (disease progression or death)
rate in the regimen containing Epivir was nine percent (80 of 935), while the event rate in the placebo containing arm was seventeen
percent (81 of 482).
The study was designed to investigate the clinical efficacy of adding Epivir to patients'
existing anti-HIV therapy, or adding Epivir to Retrovir(R) (zidovudine; AZT) for patients who were not receiving therapy
at study entry. The most common existing therapy among patients recruited into the study was Retrovir alone.
Discontinuation of the study nearly eight months early was recommended by an independent
Data Safety and Monitoring Board (DSMB) following a scheduled interim analysis of data from the trial. The recommendation
was made on the basis of data which exceeded the pre-specified requirements for possible discontinuation due to the superior efficacy
of one treatment arm. The trial's co-ordinating committee endorsed the DSMB recommendation.
"Members of the DSMB have reviewed the results of the study and unanimously recommend
the discontinuation of the trial to allow all participants access to the Epivir+Retrovir combination," said Professor Ragnar
Norrby, Chairman of the study's DSMB.
Referred to as the CAESAR trial (an acronym for the countries with investigational
sites; Canada, Australia, Europe and South Africa), the study was initiated in March of 1995 and was scheduled to conclude in March
of 1997. Patients recruited into the study had CD4 cell counts of 25 to 250/mm3 and were currently receiving one of three "background"
treatments -- Retrovir alone, Retrovir+ddI or Retrovir+ddc. Patients were then randomised to one of three regimens:
their current HIV therapy plus Epivir; current HIV therapy plus Epivir and an investigational non-nucleoside reverse transcriptase
inhibitor (NNRTI); or, current therapy plus placebo. Patients accepted into the study who were not receiving any current therapy
were treated with Epivir+Retrovir. The median time on study medication at the time of trial discontinuation was approximately
12 months.
At the pre-planned interim review, conducted on July 15, the DSMB evaluated data on
1892 patients. Adding Epivir to current therapy resulted in the 54 percent reduction in risk of disease progression or death
as compared to adding placebo. The addition of the investigational NNRTI was not shown to provide any additional benefit to that
seen with Epivir.
Surrogate marker analyses performed on a subset of patients enrolled in the trial
were consistent with the clinical results as patients receiving Epivir had more pronounced increases in CD4 cell counts and reductions
in the amount of plasma HIV levels than patients receiving placebo. However, the clinical significance of the effect of
Epivir in reducing the amount of virus in the blood is unclear.
All three arms were generally well tolerated with five percent of patients receiving
current therapy plus placebo, three percent of patients receiving current therapy plus Epivir and the NNRTI, and two percent
of patients receiving current therapy plus Epivir withdrawing from the study due to adverse events. Also, the addition of Epivir,
or Epivir plus the NNRTI, to the existing treatment regimens resulted in no additional clinical or laboratory side effects over
the control arm.
"The significant reduction in the risk of disease progression or death seen in these
data further reinforce the rationale for Epivir+Retrovir as a cornerstone of treatment for HIV and as a widely used foundation
for three-drug HIV regimens," said Richard Kent, M.D., vice president and director of world-wide clinical research for Glaxo Wellcome.
Epivir+Retrovir was generally well tolerated in clinical trials, with the most commonly
reported side effects including headache (35%), nausea (33%), malaise and fatigue (27%), nasal congestion and runny nose (20%),
diarrhoea (18%), low white blood cell counts (7.2%) and anaemia (2.7%). In addition, pancreatitis was observed in 15 percent
of paediatric patients in clinical trials, especially in children with advanced HIV disease who had received prior nucleoside
analogue therapy.
A separate study, to evaluate the effects of Epivir on delaying disease progression
or death in paediatric patients is ongoing in the U.S. That study, with a different design and treatment comparisons, is sponsored
by Glaxo Wellcome in collaboration with the AIDS Clinical Trials Group. This is a long-term trial and final results are not
expected to be available until 1999.
An interim analysis of these data will be performed and reported to an independent
DSMB when the trial is fully enrolled, which is expected in early 1997.
|
As of 8th August 1996, 3TC is a licensed drug throughout Europe for the treatment of progressive
HIV infection ( < 500 CD4/mm3 ) in adults and children over the age of 12 in combination with other antiretrovirals.
AZT + 3TC is unlikely to be a magic combination, adding 3TC to other nucleosides may confer the same advantage. Concerns also exist regarding 3TC selecting for virus cross-resistant to ddI and ddC |
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NUTRITION
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Deficiencies in vitamins B12 and E may contribute to more rapid disease progression
in people with HIV infection, according to a report from Johns Hopkins University in the United States and the Janeway Child Health
Care Centre in Canada. (see abstract Mo.C.320)
Health experts know that specific micronutrients are necessary for proper function
of the immune system, and abnormally low levels of some micronutrients have been associated with poor outcome in some HIV-infected
people. But this historical cohort study was the first to calculate the impact of low levels of vitamins A, B6, B12, and E and
folate in a large group. Johns Hopkins investigator Alice M. Tang, PhD, reported that the analysis involved 312 gay men who were
part of the Baltimore cohort of the Multicenter AIDS Cohort Study. Blood was first sampled in the cohort in 1984, and participants
were seen approximately twice yearly until the end of 1993, when the micronutrient analysis was done.
Tang and her colleagues found that men with low levels of B12 (<120 pmol/L) had an
89% increase in their risk of progression when compared with men who had adequate levels of the vitamin. Those in the lowest B12
level quartile had a twofold increase in the risk of progression compared with men in the highest quartile. The increased risk
was independent of CD4+ cell count, age, serum albumin, serum folate, use of antiretroviral therapy before AIDS, or alcohol consumption.
Study participants in the highest vitamin E level quartile (>/_1013 f:g/dL) had a
33% decrease in the risk of progression compared with those in the lowest quartile. Tang noted that vitamin E supplementation has
been demonstrated to increase circulating levels of this micronutrient, although less is known about vitamin B12 supplementation.
Low vitamin A levels were also associated with an increased risk of progression to AIDS, although that association was not statistically
significant.
Tang concluded that the association between low levels of vitamins A, B12, and E and
progression to AIDS should be studied more rigorously to determine whether supplementation can bolster the immune system and
improve the health of HIV-positive people.
Source: AidScan, July 10th, 1996 (study published in: American Journal of Epidemiology).
| Earlier studies by Tang presented at Yokohama and Berlin revealed survival advantages from increased dietary and supplementary levels of Vit B1, B2 and B6. Supplementation with ANY level of zinc was associated with increased disease progression. Forceval ô, the only NHS expense prescribable multivitamin supplement contains inadequate levels of the vitamins suggested for supplementation from these studies. Forceval ô also contains 5mg zinc per capsule. Controlled studies of an appropriately formulated nutritional supplement are needed. |