4th Conference on Retroviruses and Opportunistic InfectionsJanuary 22-26, 1997. Washington, DC. |
January 22-26, 1997. Washington, DC. |
AIDS Treatment Projects
Paul Blanchard
and
Raffi Babakhanian
were delegates at last weeks Washington Conference and the following preliminary
reports of clinical significance have been compiled by
Paul Blanchard. Due to the restricted number of places available for registration, many UK clinicians
and researchers were unable to attend this meeting. ATP hopes that the provision of these reports will be of interest to those
who were unable to attend.
Further reports, the full text of program, abstracts and other material related to
this conference can be found on the World Wide Web at the following sites:
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Combination Antiretroviral Therapy Without Zidovudine
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Zidovudine (AZT) was the first antiretroviral to be licensed for the treatment of
HIV-disease. Although now discredited as the monotherapy standard-of-care, this historical fact has led to its inclusion as a component in almost all trials
of combination therapy.
Surrogate marker and clinical end-point data generated from these zidovudine (ZDV)
trials has guided the clinical use of antiretroviral drugs, again leading to the widespread practise if including ZDV in virtually
all combination regimens.
With the increasing incidence of ZDV-resistance in recent seroconverters, reports
of worse outcome with subsequent combinations if ZDV mutations are pre-existent, and increased pathogenicity of ZDV resistant isolates,
the evidence may be building for consideration of non-ZDV containing regimens as preferred initial therapies.
Both practitioners and patients have previously considered non-ZDV containing combinations
on largely hypothetical grounds, or by cross-study comparisons of the performance of other agents in monotherapy trials.
However, either failure or intolerance has been the most usual reason up until now to drop ZDV from a combination.
The Washington Conference was notable for revealing interesting new data on non-ZDV
containing combination therapies which support the anecdotal reports of benefit from these regimens.
Rationale for the combined use of these two agents:
DIDANOSINE
- Shown to have good oral bioavailability, prolonged intracellular half-life and activity
in resting cells
- Clinically and virologically superior to Zidovudine in naive patients: ACTG 152, ACTG
175
- Clinically and virologically superior to Zidovudine in pre-treated patients: ACTG
116B/117
- Resistance infrequent in combination use with ZDV
STAVUDINE
- Good oral bioavailability and prolonged intracellular half-life
- Demonstrated clinical benefit (BMS 019)
- Clinically superior to Zidovudine in pre-treated patients with an antiviral efficacy
which is superior to Zidovudine in non-comparative studies
- Different tolerance profile to zidovudine.
STAVUDINE + DIDANOSINE
- In vitro synergy in HIV inhibition
- Good antiviral activity in naive patients ( > 1.5 log10 reduction of plasma RNA at 6 months) with good penetration into the CNS
- Rationale for first and second line double combination nucleoside analogue therapy:
need to evaluate the antiviral effect of various combinations in different populations and HIV disease stages (naive, pre-treated,
high and low plasma viral load, intermediate and low CD4 cell count)
- No available data for stavudine-didanosine combination in pre-treated patients
- Resistance infrequent (see below)
Preliminary (24 weeks) data were presented from a multicentre, uncontrolled, open-label
pilot trial involving 60 patients with CD4 >100, viral load >10,000, and more than three months of prior antiretroviral therapy
with either AZT or ddC.
Baseline characteristics included a mean age of 38.3 years, a median period of 25
months of previous antiretroviral therapy, a mean CD4 count 217 cells/mm3, mean plasma HIV load 5 log10 copies/ml.
Patients were treated with standard doses of ddI and d4T, modified according to weight.
Thirty-three patients were available at 24 weeks for analysis. Patients demonstrated sustained CD4 cell count increases (>50
cells/mm3) and viral load reduction (>1 log10 in 42%; >2 log10 in 12%; <500 copies in 15%). Three patients developed grade 2 peripheral neuropathy,
two of whom required discontinuation before week 24.
Ref: Raffi F, Auger S, Billaud E, Besnier JM, Chennebault JM, Michelet C. [Abstract
554], 4th Conference on Retroviruses and Opportunistic Infections, 1997.
Interim results were presented from an open-label pilot study involving patients with
CD4 counts of 50-350 who were not eligible for ZDV therapy due to intolerance or treatment failure. All were treated with standard
doses of ddI/d4T, modified according to weight. Twenty-five patients were enrolled, and 21 were evaluable at week 12.
Mean baseline values included age 40.2 years, prior ZDV monotherapy of 18 months,
CD4 count of 116.2 cells/mm3 and plasma HIV RNA of 5.3 log10 copies/ml.
Viral load declined by 0.9 log10 and CD4 cell count increased by 45 cells/mm3 by week 12. Three patients developed reversible peripheral neuropathy. For 12 patients
who were evaluable at week 24 viral load had declined by 0.9 log10 and CD4 count increased by 38 cells/mm3. The % of patients with viral load below the limit of detection ( < 500 copies/ml)
was 33% across the 24 weeks.
A total of 4 adverse events led to therapy being discontinued. There were 3 cases
of sensitive peripheral neuropathies and 1 asymptomatic grade 2 amylase elevation. All adverse events resolved completely after
therapy was discontinued.
In spite of the fairly advanced and pre-treated status of the patients, the therapy
was well tolerated and led to a substantial decrease in viral load and an increase in CD4 counts.
Ref: Durant J, Rahelinirina V, Delmas B, Dupr F, Carmagnolle MF, Halfon P, et al. [Abstract 553], 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
Another open-label trial of ddI/d4T involved 14 patients with a history of at least
three months of prior antiretroviral therapy. Mean viral load reduction was 1.4 log10, and mean CD4 increase was 45 cells/mm3 at eight weeks. Viral load reached undetectable levels (< 500 copies/mL) in six patients
and remained undetectable in four at eight and 20 weeks. Neurotoxicity was observed in 3 patients with one of these requiring
permanent discontinuation of the drugs. The authors concluded that ...the combination is a viable and effective option for antiretroviral therapy that
can achieve undetectable plasma HIV levels in some patients. However, the potential for significant neuropathy exists in some
patients. The duration of response has not been established.
Ref: Kalathoor S, Sinclair J, Andron L, Sension MG. [Abstract 552], 4th Conference
on Retroviruses and Opportunistic Infections, 1997.
| Initial results from the dose escalation study with d4T/ddI in treatment na ve persons were presented at Vancouver 1996. Reductions of around 1.1-1.8 log represent a similar effect to that observed with other 2 NA combinations. The attractions of this particular combination lies in the low frequency of resistance seen at I year of therapy. Additionally drugs with proven second-line benefit such as 3TC are saved for later use. |
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The first study of d4T resistance during monotherapy, (Lin et al. J Inf Dis, 1994)
showed d4T resistance at > 1 yr of monotherapy in 3/13 persons na ve to previous therapy. ZDV resistance also arose in 5/13 and ddI resistance in 3/13.
No consistent genotypic pattern was observed. Whether d4T exposure led to ZDV and/or ddI resistance or whether study subjects
could have exposed themselves to these agents surreptitiously is unclear. No other published study has looked at this issue. As the d4T molecule (unlike ZDV and 3TC) is smaller than the natural substrate for reverse transcriptase (ie. DTTP), it is more difficult for resistance to develop (as with ddC and probably ddI). ZDV resistance has previously been reported to persist after stopping therapy for more than 1 yr despite ddI therapy. The concern raised by the Soriano paper is that the (presumably) pre-existent ZDV mutations persisted because they provided this virus with an advantage in the presence of d4T. ZDV resistance has previously been reported to be associated with d4T resistance in 1/11 clinical isolates. |
The rationale for combining hydroxyurea (HU) with ddI came from in vitro studies that
indicated a synergism between the two compounds in the inhibition of HIV. The antiviral activity of d4T is also enhanced when
combined with HU. Reports at Vancouver on the use of the combination in small numbers of patients were promising with reported
sustained viral load reductions averaging 1 log10. In one study (Biron, abstract Th.B.291, 1996) 6/10 patients had sustained an undetectable
plasma viraemia out to 360 days on the combination of ddI/HU.
The Washington Conference saw the first reports of using hydroxyurea together with
the double nucleoside combination d4T/ddI.
In this study 101 patients with the baseline parameters - median age 34 yrs, median plasma RNA 4.6 log10, median CD4 count 339 cells/mm3, were randomised to receive ddI 200mg bid + d4T 40mg bid + placebo or ddI + d4T +
hydroxyurea 500mg bid. 80% of patients were antiretroviral naive. The study is ongoing and unblinded results were presented for
100 patients, 92 of whom are evaluable out to week 12.
At 12 weeks HIV RNA (Roche assay, lower limit of detection 20 copies/ml) had fallen
1.8 log10 in the placebo group compared to 2.2 log10 in the hydroxyurea arm (p=0.04). 32% of subjects had less than 200 copies/ml in the
placebo arm while the hydroxyurea containing arm had 55% of subjects below this limit of detection (p=0.04).
CD4 count changes from baseline at week 12 were +91 and +10 cells cells/mm3 in the placebo and HU arms respectively. However, when looked at as CD4% these figures
were +2.8 and +3.4, reflecting the fall in total lymphocyte count of 205 cells/mm3 in the HU containing arm ( + 69 in the placebo group).
In conclusion the authors state ...addition of HU to ddI+d4T produced a more profound decrease in HIV-1 viraemia and
an increased proportion of patients with viraemia < 200 copies/ml. No increase in CD4 cells was observed in patients treated
with hydroxyurea compared to a mean increase of 91 cells in patients receiving ddI+d4T. (However),... an increase in CD4/CD8 ratio
was observed in both groups. The lack of effect on CD4 counts can be explained by hydroxyurea-induced lymphopaenia.
Ref: Rutchmann OT, Opravil M, Iten A, et al. [Abstract 550] 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
A further study (Abstract 549) also observed neutropaenia (absolute neutrophil count
< 700/ul) in patients treated with HU who started therapy with neutrophil baseline counts below 1,700/ul. This neutropaenia was
reversible after withdrawal of HU and counts were maintained at baseline values while continuing on ddI+d4T. In four patients
out to week 12 in this small study a mean viral RNA reduction of 1.9 log10 was sustained.
|
Hydroxyurea has not proven popular in the UK due to nausea and common haematological
toxicitys. However, Viral load reductions are impressive for a non-PI containing combination.
One possible strategy to limit haematological impact could be the inclusion of HU in an initial combination in an attempt to
maximise viral load reductions, then its withdrawal from the regimen when viral load has fallen below the limit of detection. Further
investigation of differing doses and such strategies with HU appear warranted. |
Several papers at the 4th Retrovirus Conference presented data on the antiviral efficacy
of the combination of D4T and 3TC. These data were anxiously awaited, since this regimen had become very widely used before
trials were available proving that it was effective. Fortunately, we can now say that the combination appears to be active,
particularly among patients who have never taken either drug. Although direct well-controlled comparisons are limited, this combination
appears to compare favourably with AZT plus 3TC. Adding D4T to patients who have already received AZT and 3TC however seems
to have only a modest effect (Abstract LB5).
Dr. Christine Katlama from the Hopital Pitie Salpetriere in Paris presented a late
breaker (Abstract LB4) on two pilot studies of D4T plus 3TC (Altis 1 and Altis 2). Altis 1 involved antiviral naive patients with
a median CD4 count of 258 and median viral load at baseline of 76,502 copies (about 4.8 log10). The maximal viral load response was about 2.0 log10 and at 24 weeks, there was a sustained reduction of 1.66 log10 accompanied by a CD4 rise of about 100 cells. In Altis 2, the patients were pre-treated
with AZT, ddI , and ddC, but had to be naive to d4T and 3TC. These patients had slightly more advanced disease with baseline
median CD4 count of 172 and median viral load at baseline of 91,000 copies (about 4.9 log10). The responses to D4T plus 3TC were more modest in this group with a maximal viral
load decrease of 1.4 and CD4 increase of about 50 cells. By week 24, the viral load decrease was about 0.5 log10 below baseline. Among the naive patients, 21% had undetectable viral loads at week
24 (using the standard Amplicor assay). Toxicity was limited and only 1 patient discontinued D4T due to neuropathy. These results
were quite comparable to results from the 4 pivotal trials for AZT plus 3TC, presented as late breakers at this meeting 2 years
ago.
A head to head comparison of AZT plus 3TC with D4T plus 3TC focusing on the antiviral
effect and drug levels in the cerebrospinal fluid was reported in another late breaker presented by Dr. Foudraine from the University
of Amsterdam (Abstract LB5). They randomised 31 drug naive patients to begin either D4T plus 3TC or AZT plus 3TC and performed
lumbar punctures at baseline and at week 12. The change in plasma viral load in both groups was similar. Fifteen patients
had lumbar punctures; all had detectable virus in their CSF at baseline. By week 12, all had undetectable CSF viral RNA and
negative cultures. Drug levels in the CSF were 41, 56, and 67ng/mL for AZT, D4T, and 3TC respectively. Absolute drug levels in the
CSF relative to the concentration needed for antiviral activity may be more telling than blood to CSF ratios, which are commonly
reported. When one drug has rapidly changing blood levels over the dosing interval (as in the case of AZT) the reported ratio
may be very dependent on the timing of specimens. The Amsterdam group speculated that both D4T plus 3TC and AZT plus 3TC would
be expected to protect against HIV-related dementia. The effects of protease inhibitors on CSF viraemia are less clear, and one
consideration in the design of triple combination regimens may be the inclusion of drugs with good activity in this compartment
Several posters also confirmed the activity of D4T plus 3TC. A pilot open label trial
of 41 patients performed in at the BC Center for Excellence in Vancouver yielded similar results (Abstract #557). Importantly,
viral load reductions were greatest among those who had not received either drug and were least among patients who had been treated
with 3TC. Cal Cohen from Community Research Initiative of New England presented a retrospective study of 330 patients (abstract
# 556). The median initial viral load response was 1.1 log10, and as in the Vancouver study, patients who had already received AZT and 3TC had
a significantly reduced response.
Each of these studies has at least one major limitation, including small sample size,
lack of randomisation, lack of concurrent controls, or retrospective data collection, but taken together they paint a consistent
picture.
Author: Andrew Pavia, M.D.
Source: The Body
|
2 posters showed a limited relationship between CSF viral load and cognitive function.
The value of changes in CSF viral load to HIV-related dementia are also, at best, unclear at present. About 29% of d4T, relative
to plasma, was achieved in the CSF. This is not dissimilar to ddI or ddC and these drugs may also have neuroprotective effects.
Studies of PIs and dementia are awaited but limited CSF penetration does not rule out a CNS effect
in drugs which are highly protein bound. |
This open label study suggested that combination therapy with d4T+3TC+IDV could be
of benefit to previously treated, severely immunocompromised patients.
Baseline values for 145 patients included mean CD4 count of 84/mm3, mean viral load of 5.17 log10, and mean duration of previous nucleoside analogue use of 36 months (89.5% ZDV, 70.8%
ddI, 56.2% ddC, 58.3% 3TC, 31.9% d4T). 73 patients had AIDS-defining events before the initiation of triple therapy. At week
8 a rise in mean CD4 to 142/mm3 and a fall in mean viral load of -1.62 log10 was seen. 43% of evaluable patients at week 8 had viral load <500 copies/ml. The
combination appeared to be well-tolerated with only 3 patients discontinuing therapy due to adverse events.
Ref: Truchis P de, Zucman D, Dupont C, et al. [Abstract 247] 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
This open label study enrolled 33 adults with baseline characteristics - mean CD4
count 252 cells/mm3, mean plasma HIV RNA 4.63 log10. Ritonavir was given alone for 14 days and then weight adjusted doses of ddI and
d4T were added to the regimen. At week 12 results were available for 17 patients and a reduction in viral load of 2.14 log10 and an increase in CD4 count of 138 cells/mm3 had occurred. 6 patients left the study during the first 5 weeks due to adverse events.
The authors conclude that ...three months of ritonavir in combination with d4T and ddI as a first line treatment
produced a significant reduction in the plasma HIV-1 RNA load and infectious blood cells.
Ref: Landman F, Damond P, Detruchis C, et al. [Abstract 246] 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
A total of 22 subjects who were treatment-naive to d4T, ddI and protease inhibitors
were enrolled to receive d4T 40mg bid, ddI 200mg bid and nelfinavir 750mg tid for 12 weeks. At baseline median CD4 count was
315 cells/mm3 and median viral load 4.75 log10. Eleven subjects had received prior treatments with NAs other than ddI or d4T.
For eight evaluable subjects at week 8 there had been a change in median CD4 count
of +218 cells/mm3, and a fall in mean HIV plasma RNA of -2.1 log10. 3/8 subjects at week 8 had viral load <500 copies/ml. No pharmacokinetic interactions
were noted and the combination was well tolerated.
Ref: Pedneault L, Elion R, Adler M, et al. [Abstract 241] 4th Conference on Retroviruses and Opportunistic Infections, 1997.
|
Nelfinavir resistance, mediated through a substitution at codon 30 does not result
in cross-resistance to other P.I.s, favouring early use. Indinavir and ritonavir may frequently select for virus cross
resistant to nelfinavir. Nelfinavirs good tolerability, favourable resistance profile and non-food dependent administration
also make it an attractive choice. Additionally, reported drug interactions appear to be infrequent (so far) with this P.I. |
Many extensively pre-treated patients have been following closely any research results
which may indicate favourable results from the as yet untried combination of protease inhibitor and NNRTI. Pharmacokinetic
data released previously by the companies was presented at this conference. The interactions of both nevirapine and delavirdine
with all three currently licensed protease inhibitors (Abstracts 372 & 374) were explored allowing patients and physicians to consider
combining these two different classes of compounds.
An intriguing report from Canada on the use of such a combination in patients who
have received extensive prior combination antiretroviral therapy could herald encouraging news for this avenue of treatment.
21 patients were identified who were experiencing HIV disease progression despite
extensive prior antiretroviral therapy, and/or unmanageable drug-related toxicitys. Salvage therapy was attempted with a novel combination of IDV 800 mg q8h, NVP 200mg
daily for 14 days then 200mg bid, and 3TC 150mg bid.
Baseline mean viral load was 5.13 log10. Eight week data reported in the abstract shows a change from baseline of mean viral
load of -2.35 log10 with 50% of subjects achieving a viral load <500 copies/ml. During an oral session
(Abstract 374) data updated to 20 weeks from this study were released. For 12 individuals who were out to 20 weeks the mean viral
load change from baseline was -3.0 log10, CD4 count was +100 CD4 celss/mm3 and CD8 cells had increased by 400 cells/mm3. Even more dramatically, when an ultrasensitive PCR test was used to measure plasma
viral RNA down to 20 copies/ml, 60% of the participants had fewer than 500 copies/ml and 15% were below 20 copies/ml. These results
appear to be unprecedented in such an advanced and heavily pre-treated cohort.
Ref: Harris M, Durakovic C, Conway B, et al. [Abstract 234] 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
|
Nevirapine reduces IDV bioavailability which has led to a suggestion to raise doses
to 1000mg q8h if these two agents are combined. 1000mg q8h of IDV appears to be safe and well tolerated in early dose-ranging
studies. This small study appears to suggest that virological response may not be compromised by the adverse pharmacokinetic interaction.
NNRTI/PI combinations will need careful consideration of these interactions to avoid any negative influence on activity. |
John Mellors from the University of Pittsburgh gave one of the most compelling oral
presentations at the 4th National Conference on Human Retroviruses and Opportunistic Infections in Washington, D.C. when he addressed
the issue of combining two protease inhibitors. The potential advantages which he outlined include the more durable HIV
suppression which may be achievable, a delay in the emergence of viral resistance, divergent resistance patterns, favourable drug-drug
interactions, the potential for lowering doses and twice daily dosing schedules. The potential disadvantages include the
in vitro antagonism which has been observed in some experiments (indinavir + saquinavir), more frequent occurrence of adverse effects,
HIV escape into the central nervous system and the greater cost. Dual protease trials are ongoing with ritonavir and saquinavir,
nelfinavir and saquinavir, ritonavir and nelfinavir, nelfinavir and indinavir and are planned for 15 additional other combinations.
The clinical trial which has produced most exciting data has been the multicentre
study evaluating four dose combinations of ritonavir and saquinavir in protease naive patients with CD4 counts 100-500 cells/mm3. The doses studied included twice daily regimens of saquinavir and ritonavir at either
400 or 600 mg and a thrice daily regimen with 400 mg twice daily of each drug. The most frequent side effects seen have been
diarrhoea with the higher dose levels as well as liver function test abnormalities. The highest rate of drug discontinuation
has been in the thrice daily regimen. In addition a relationship has been noted between pre-existing liver disease (Hepatitis B
or C) and subsequent transaminase elevations in the combination trial. Viral load responses have been excellent, with 70-80% of
patients remaining below the level of detection at 24 weeks of follow-up and CD4 responses of 90-100 cells. The few patients who
were not completely suppressed were investigated for compliance patterns and many were found to be nonadherent to their medication
regimens. Of those who were compliant 90% and 97% respectively were < 200 or < 1000 copies/ml.
Dr.Mellors also noted that the maximal viral load response is predictive of the durability
of the treatment response, with those able to maintain viral levels <200/mm3 maintaining their response for the longest. This argues in favour of trying to achieve
the greatest amount of suppression with the most potent agents since it may predict the most durable response and overall
achieve the desired goal with the least number of agents and the fewest side effects.
Author: Ramon Torres, M.D.
Source: The Body
Two small studies presented at the National Conference on Retroviruses and Opportunistic
Infections in Washington, D.C. examined the effect of the combination of ritonavir and saquinavir in advanced HIV positive
patients. Prior to these studies, the combination of ritonavir and saquinavir had been reported to exert a very potent antiretroviral
effect in protease inhibitor naive patients, with over 3 log10 reductions in HIV RNA viral load and over 150 CD4 cell increases after 20 weeks of
therapy.
In the first observational study conducted by Steinhart and colleagues from Miami,
Florida (Abstract 199) 10 antiretroviral experienced patients with a mean CD4 count of 60 cells/mm3 not responding to combination therapy with nucleoside analogues and intolerant to
the recommended doses of ritonavir (600 mg twice daily) were continued on their nucleoside regimen and given saquinavir (800 mg
twice daily) and ritonavir (400 mg twice daily). After a mean length of follow-up of 5.2 months CD4 counts increased in 9 of the
10 patients with a mean percentage increase of 275% and HIV RNA became undetectable (< 500 copies/ml) in 5 of 10 patients. No
opportunistic infections occurred and there were no adverse effects or laboratory effects of treatment.
In a second study presented by Barbour and others from the Desert AIDS Project in
Palms Springs, California (Abstract 245) 32 HIV positive patients with CD4 counts < 250 cells/mm3 were treated with ritonavir (600 mg twice daily) and saquinavir (400 mg twice daily)
and two nucleoside reverse transcriptase inhibitors. All had baseline HIV viral loads > 5,000 copies of RNA/ml or evidence of
disease progression despite 4 months of triple therapy (2 nucleoside analogues and one protease inhibitor).
Baseline CD4 count on average was 79 cells and HIV RNA viral load was 4.86 log10. After 4 weeks of therapy with the four drug combination 53% of patients had achieved
a reduction in viral load below the level of detection at 400 copies/ml, which persisted for 8 subsequent weeks. The mean increase
in CD4 count was 72 cells at 12 weeks. Two patients withdrew because of side effects
These two studies suggest that the combination of ritonavir and saquinavir (using
lower doses of either one) may be effective in patients with either intolerance to higher doses or evidence of virologic or clinical
failure on triple protease inhibitor containing combinations. Further studies of this combination in protease-experienced patients
are urgently needed.
Author: Ramon Torres, M.D.
Source: The Body
|
Saquinavir + ritonavir is now a popular combination at some UK centres for persons
intolerant to nucleoside analogues (such as due to peripheral neuropathy). After 4-8 weeks of therapy ritonavir intolerance problems
diminish and most people who manage the first month achieve good clinical response. However, as observed by Hirschel et al
at Washington, some persons with advanced disease, extensive prior therapy, and imperfect adherence may fail with a dual resistant
virus. Theoretically better tolerated PI/PI combinations such as saquinavir-nelfinavir are now under investigation, with preliminary
data suggesting similar virological effects to SQV-RIT. |
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OTHER REPORTS
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Three studies presented at the 4th National Conference on Retroviruses and Opportunistic
Infections in Washington, DC reported dramatic decreases in inpatient and outpatient hospital utilisation by patients with
HIV infection at the largest AIDS Centre in New York, a large group private practice in Los Angeles, and 9 centres in France.
The studies reported declining numbers of hospital admissions coincident with the advent of combination retroviral therapies, which
included protease inhibitors. The major effect of hospital, hospice and home care utilisation was observed during 1996, when
protease inhibitors became widely available to the general population. At St. Vincent's Hospital and Medical Center of New York,
where the numbers of hospital admissions for HIV-related illness had been continually increasing since the mid-1980s, a 10.5%
reduction in admissions was observed from 1995 to 1996, in addition to a 2.5 day reduction in average length of hospital stay, and
a 24% decrease in average monthly AIDS census. This was accompanied, however, by a dramatic increase in ambulatory visits (33%),
and a 21% increase in individuals seeking health care at the Centre. Antiretroviral drug utilisation and inpatient pharmacy
costs increased ten-fold, suggesting that the factor most related to the changing trend is the increasing use of antiretroviral
combination therapies. "With the shortening of the average length of hospital stay, our patients' quality of life and productivity
has been greatly improved," said Dr. Ramon Torres, who conducted the study.
In Los Angeles, Dr. Peter Ruane reported a 56% reduction in episodes of hospitalisation
and home care over the base year of 1994. 80% of the patient population in the group practice (N=450-500) experienced rises
in CD4 counts in 1996 as compared to 1995, with fewer patients (17.3%) having dangerously low counts (<50) in 1996 as compared
to 1995 (28.5%). Dr. Ruane also reported a downward trend in AIDS-related deaths from 1993 to 1996 among the patients in the practice,
which was more evident in the last quarter of 1996, which probably reflects the decline in the number of opportunistic infections
and malignancies suffered by patients as their immune systems improve on the potent antiretroviral treatments.
Patients also required fewer costly AIDS related treatments such as Neupogen, erythropoetin
and CMV therapy and fewer speciality referrals than in the pre-protease era.
In France at 9 AIDS reference centres the same trends were evident; in a study of
7,391 patients followed from September 1995 to October 1996, increasing percentages were placed on triple combination therapies,
which included protease inhibitors. At four of the centres decreases in AIDS defining events were observed, whereas at two additional
centres there were no increases. This was related to the higher percentage of patients on triple therapies at the group of
4 centres. The money saved by the difference between hospitalisations that were avoided and the cost of the antiretroviral treatments
was estimated at $650,000 at the four centres where the triple therapies were being widely utilised.
Another study presented at the conference utilised a mathematical model to project
the cost effectiveness of triple combination therapy with indinavir, AZT and 3TC. In this study, conducted by Cook and others from
Merck Pharmaceuticals, makers of indinavir, disease progression was estimated according to data from a triple combination therapy
trial being sponsored by the company, which compared the triple combination with indinavir alone, and the dual combination
of AZT and 3TC. The cost-effectiveness was estimated from the length of suppression of viral replication observed in the trial,
which was expected to extend beyond the clinical trial follow-up period. The incremental cost per year of life gained was estimated
to be under $10,000 for indinavir alone, $30,000 for the triple combination compared to AZT and 3TC. The model suggested that
initiation of indinavir alone, and in combination before the first AIDS-defining illness will increase survival compared to AZT
and 3TC a cost that is generally acceptable by cost-effectiveness standards.
These studies all indicate that the overall impact of the potent combination antiretroviral
therapies is beneficial to both the health care providers and the patient, as the former are able to lower hospital costs
and maximise outpatient care, and the latter have improved quality of life and productivity as they spend less time lying in
hospital beds, losing productive days from work, school or other activities.
Ref: Ramon Torres, M.D.
Source: The Body
|
The next Issue of AIDS Treatment Projects DocFax will focus on presentations at the Washington Conference indicating possible
immune reconstitution and resolution of opportunistic illnesses with Highly Active Antiretroviral Therapy (HAART) as well as
further reports on antiviral therapy in late stage HIV-disease. |