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EPIDEMIOLOGY
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Deaths and inpatient admissions at large London HIV treatment centres have also declined.
Additionally, the number of people seeking treatment has, anecdotally, increased.
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ANTIVIRALS
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These findings are in keeping with the virology subset analysis of ACTG175 which indicated
a strong correlation between viral load reductions on therapy and hard clinical endpoints - development of AIDS or death (see ATP DocFax Issue 10). |
Research supported by the National Institute of Allergy and Infectious Diseases (NIAID)
has demonstrated that in patients with advanced HIV disease the combination of indinavir plus two nucleoside analogue reverse
transcriptase inhibitors (RTIs) is significantly more effective in reducing the occurrence of AIDS-defining illnesses or death
than two RTIs alone. The study, known as ACTG 320, was designed to determine the efficacy and safety of the protease inhibitor
indinavir when given in combination with zidovudine (ZDV) [or stavudine (d4T)] and lamivudine (3TC), as compared to ZDV (or d4T)
plus 3TC.
Previous trials have shown clinical benefit for combinations containing the protease
inhibitors saquinavir or ritonavir, but this is the first demonstration that the surrogate marker responses seen with indinavir
containing combinations translate to clinical benefit.
"The results of ACTG 320 confirm the importance of including protease inhibitors in
treatment strategies for patients with advanced HIV disease," says Anthony S. Fauci, M.D., NIAID director. "Significantly, the
current study provides additional evidence that combination approaches using protease inhibitors can reduce the risk of death."
Preliminary results of the study were reviewed Feb. 18, 1997, by an independent data
and safety monitoring board, which recommended early termination of enrolment and closure of the study. They based this recommendation
on the significant benefit of the triple combination including indinavir in delaying disease progression and death. "The
further, significant reduction in disease progression conferred by indinavir when given as part of a three-drug combination
illustrates the rapid progress that the field of HIV therapeutics has made in the last two years and suggests that further benefits
can be achieved with regimens of ever-increasing potency," commented Scott Hammer, M.D., protocol chair of ACTG 320.
Volunteers in the study had CD4+ T cell counts below 200 per cubic millimetre (mm3) of blood at study entry and had taken ZDV for at least three months, but had received
less than one week of 3TC and no protease inhibitors. The mean baseline CD4+ T cell count of the participants was 86 cells/mm.3 They were randomised to receive either the combination of ZDV (600 mg/day), 3TC
(300 mg/day) and indinavir (2400 mg/day), or ZDV plus 3TC plus placebo. Participants intolerant to ZDV could use stavudine (d4T),
and those developing toxicitys or experiencing mild disease progression were allowed to change to other approved
nucleoside analogues. The majority of participants received ZDV and 3TC for the duration of the study.
A total of 1,156 HIV-infected volunteers participated in ACTG 320. Participants were
enrolled at 33 sites of the NIAID-supported AIDS Clinical Trials Group, and at seven sites of the National Haemophilia Foundation.
They were followed for a median of 38 weeks, with some patients being followed for up to one year. Further studies are needed
to understand the long-term impact of this triple combination. Sub-studies of ACTG 320 are currently being analysed, including
a study of how the various treatments affect the amount of virus in patients' blood and to characterise the development of drug
resistance in the different treatment arms.
Survival and a delay in disease progression were significantly better in patients
receiving triple combination therapy. In that group, AIDS-defining illnesses, including opportunistic infections and cancers, and
deaths were decreased by approximately half. Sixty-three instances of disease progression (including AIDS-defining illnesses
and deaths) occurred in volunteers on the ZDV/3TC arm versus 33 in volunteers on the triple combination arm. The benefit was statistically
significant for the subset of patients with CD4+ T cell counts less than 50/mm3 and there was a similar trend for patients with CD4 counts between 50 cells/mm3 and 200 cells/mm3. There were 18 deaths in the double therapy arm versus eight deaths in the triple
therapy arm.
In addition, the safety of each treatment regimen was closely monitored. There were
no major differences in the safety or toxicity of the two treatment regimens and the study medications were well-tolerated.
Source: NIAID
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All three currently licensed protease inhibitors have now demonstrated improvement
in survival and delay in disease progression when used in combination with nucleoside analogues. In patients with advanced disease
(CD4 < 50 cells/mm3 ) both ritonavir and now indinavir have had a clear impact on clinical end-points.
In addition, (in patients with mean CD4 150-170 cells/mm3 ) saquinavir + ddC reduced death by 72% relative to the clearly suboptimal regimens
of either saquinavir or ddC monotherapy. This study confirms that in ZDV experienced patients, the inclusion of indinavir + 3TC reduces death by around 50% relative to adding 3TC alone, with no additional toxicity. Smaller studies such as Merck 035 had previously indicated that, in ZDV experienced persons, adding indinavir + 3TC substantially and sustainably reduced viral load relative to adding 3TC, the majority of persons in that study going undetectable. It is somewhat surprising, therefore, that in this ACTG 320 study 33 patients (6%) in the triple combination arm became ill or died over a mean 38 weeks of follow up. Why this occurred may be answered by resistance substudies currently under analysis and by assessment of treatment compliance. This, and the following study confirm that inclusion of indinavir represents potent salvage therapy for patients failed on initial regimens. Data are now awaited on the use of P.I.s as part of initial therapy regimens. |
A landmark study evaluating the safety and efficacy of indinavir (Crixivan) in combination
with AZT and 3TC in patients with advanced AIDS and CD4 counts < 50 cells/mm3 was presented at the 4th National Conference on Human Retroviruses and Opportunistic
Infections in Washington D.C. by Dr. Martin Hirsch from Massachusetts General Hospital. The study was a randomised, double-blind
24 week trial which enrolled 320 patients with at least 6 months of prior AZT therapy and a median CD4 count of 15 cells/mm3. Patients were randomised to receive indinavir (800 mg every 8 hours) in combination
with AZT (200 every 8 hours) and 3TC (150 mg twice daily), Indinavir monotherapy or AZT + 3TC. All patients were protease inhibitor
and 3TC naive.
After 6 months of follow-up 65% of 85 patients evaluable for analysis in the triple
combination arm had experienced declines in viral load to below the level of detection (500 copies/ml), whereas 2% on indinavir
monotherapy and none of the patients in the AZT + 3TC arm experienced HIV levels below the level of detection. The median decreases
in viral load at 24 weeks were -2.2 logs for the triple therapy arm, -0.5 for the indinavir monotherapy arm and -0.2 for the
AZT + 3TC arm. Median increases in CD4 counts at 24 weeks were + 84 cells for the triple combination, + 65 cells for indinavir
monotherapy and zero cells for AZT + 3TC. Overall more patients withdrew from the AZT + 3TC arm of the study (35), as compared
to the other two arms (23 and 17 for the indinavir monotherapy and triple combination arms, respectively). Only one patient developed
a kidney stone which required drug discontinuation. The study has been extended and all patients have been offered triple
combination therapy.
Ref: Hirsh M, Meibohm A, Rawlins S, Leavitt R. [Abstract LB7], 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
Author: Ramon Torres, M.D.
Source: thebody
Dr. Dan Stein and colleagues from Albany Medical Center in New York reported the long
term data from Merck trial 021, a study which compared three doses of indinavir (800 mg thrice daily, 1000 mg thrice daily and
800 mg every 6 hours) in an antiretroviral experienced patient population with CD4 counts between 150 and 500 and HIV RNA titres
> 20,000 copies/ml. Fifty six patients with average baseline CD4 counts of 240 and HIV RNA levels of 4.59 logs were randomised
to one of the three dosage arms and followed for 96 weeks. For the first year the patients were maintained on indinavir monotherapy,
and zidovudine was added during the second year. The percents of patients with undetectable viral were 30%, 61.5% and 58.3%,
respectively. The median viral load reductions were 1.34, 1.64 and 1.85 logs, respectively. In regards to CD4 count elevations,
the 3 arms had rises of CD4 cells greater than 150 at 96 weeks, with average rises of 150, 230 and 230 respectively. Six patients
discontinued therapy; 3 due to nephrolithiasis, one due to taste perversion, two due to hyperbiirubinaemia and one due to
thrombocytopenia. Overall, 13 of 56 (23%) experienced nephrolithiasis, although after adequate hydration was instituted, the incidence
of renal stones declined. This is the longest term study of indinavir therapy, which demonstrates the durability of the
antiretroviral and immune boosting effect of this protease inhibitor in antiretroviral experienced patients.
Ref: Stein D, Drusano G, Steigbigel R, et al. [Abstract 195], 4th Conference on Retroviruses
and Opportunistic Infections, 1997.
Author: Ramon Torres, M.D.
Source: thebody
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The two year data from the 021 study underline the substantial and sustained antiviral
activity of indinavir. However, this study also raises serious concerns about the currently recommended dose of indinavir (800mg every 8 hrs). This study suggests that higher doses may produce greater reductions in viral load, maintain more patients below 500 copies/ml and lead to greater increases in CD4 over 2 years of follow up. These dose/response observations and their implications for the durability of antiretroviral effect should alert licensing authorities to a re-evaluation of the currently recommended dosing levels of indinavir. The high incidence of nephrolithiasis, 23% over 2 years, is also at odds with the 5% reported in indinavir package inserts. |
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OPPORTUNISTIC ILLNESS
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MDRTB remains infrequent in the UK, although several London hospitals have reported
outbreaks. Treatment, whilst improving, is problematic due to tablet load, need for IV or IM medications in some and drug tolerability.
Additionally, the potential for interaction between TB drugs and PIs may complicate the management of both the HIV-disease and the TB. |
The results of two multicentre trials that appear in the Annals of Internal Medicine
indicate that intravenous cidofovir can successfully delay progression of cytomegalovirus retinitis (CMV) in AIDS patients.
In the first study, Dr. Jacob P. Lalezari of Quest Clinical Research in San Francisco
and colleagues randomly assigned 48 AIDS patients with previously untreated peripheral CMV retinitis to receive immediate or
delayed treatment with intravenous cidofovir. Along with intravenous cidofovir, which was administered at 5 mg/kg once a week for
2 weeks and then once every other week, subjects also received oral probenecid and intravenous hydration to minimise treatment-related
nephrotoxicity.
Dr. Lalezari found that the median time to progression of CMV retinitis was 120 days
in the immediate-treatment group compared with 22 days in the deferred-treatment group. "Neutropenia (15%) and proteinuria (12%),
both asymptomatic, were the most common serious adverse events considered to be possibly related to cidofovir."
He points out that the cidofovir regimen is more convenient than daily intravenous
ganciclovir or foscarnet. However, he also stresses that careful predose monitoring for signs of renal tubular dysfunction, along
with concomitant administration of oral probenecid and intravenous saline hydration, are important to minimise toxicity.
In the second study, members of the HPMPC Peripheral Cytomegalovirus Retinitis Trial
reached similar conclusions. In this two-stage, multicentre Phase II/III trial, researchers administered intravenous cidofovir,
also referred to by the chemical abbreviation HPMPC, to 64 AIDS patients who had small, peripheral CMV retinitis lesions. The
subjects, who also were previously untreated for CMV retinitis, were divided into three groups: high-dose cidofovir, low-dose cidofovir,
or deferred treatment. Hydration and probenecid were also administered to reduce treatment toxicity.
They found that the "...median time to progression was 64 days in the low-dose cidofovir
group and 21 days in the deferral group." With high-dose cidofovir, the "...median time to progression was not reached."
These results "...suggest that both high-dose and low-dose cidofovir, given as intermittent
intravenous infusion, are effective in controlling CMV retinitis" Like the first group, these investigators also recommend
coadministration of probenecid and hydration, which reduced but did not completely prevent nephrotoxicity. Overall, they believe
that cidofovir is a "...valuable addition to the list of therapies available for CMV retinitis."
Ref: Ann Intern Med 1997;126:257-274.
Source: Aegis
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Cidofovir is an exciting addition to the range of anti-CMV treatments due to its proven
activity and more convenient administration relative to foscarnet and IV ganciclovir. However, patients require careful monitoring
particularly for renal toxicity and the coadministration of probenicid to limit renal toxicity may itself cause side effects
(nausea, rash). Whilst some units may use cidofovir first line for CMV (due to convenience of administration) new oral anti-CMV
drugs (pro-oral ganciclovir, lobucavir and possibly cyclical-cidofovir) are likely to become the mainstay of maintenance therapy. |
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PATHOGENESIS
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HIV-positive men seem to develop AIDS more quickly if they are deficient in vitamin
B-12, Johns Hopkins University researchers reported Friday. Among 310 homosexual and bisexual men infected with HIV, those with
adequate levels of the vitamin did not progress to AIDS for about eight years, compared to four years for those with deficient
vitamin levels. The researchers, led by Dr. Alice M. Tang, also found that vitamin B-6 and folic acid had no similar association
with disease progression. Tang said that further study was needed to confirm the link and to "see if improvement in the levels
of nutrients like B-12, with vitamin supplements, delays disease progression." The study results were published in the February
issue of the Journal of Nutrition.
Source: AIDS Daily Summary
Although patients who have recently developed AIDS are more likely to survive an AIDS-defining
illness, the long-term prognosis for these patients has not changed, according to a report by London researchers.
Dr. Andrew N. Phillips, a statistician, and members of the Royal Free/Chelsea and
Westminster Hospitals Collaborative Group evaluated data for more than 2,600 AIDS patients who were followed between 1987 and 1995.
The study contained data on approximately 20% of all AIDS patients in Great Britain. It is largest of its kind that is not based
on surveillance data, Dr. Phillips said. The data, which were collected in a clinical setting, are more detailed than those
typically available from surveillance databases, he explained.
In the 3-month period following the initial AIDS-defining illness, patients diagnosed
with AIDS after 1987 had a significantly lower risk of death compared with patients diagnosed with AIDS before 1987, the team
reported. However, after this 3-month period there were no differences in the risk of death according to year of diagnosis.
The average patient CD4 lymphocyte count at time of AIDS diagnosis declined over time.
The implication is that HIV-positive patients are" ...going longer before they develop AIDS," The average CD4 lymphocyte count
at time of AIDS-defining illness, using CDC criteria, was 90 in those diagnosed at or before 1987, compared with an average
CD4 lymphocyte count at time of AIDS-defining illness of 40 in the 1994-to-1995 period.
Similarly, there were changes in the pattern of AIDS-defining illnesses. Over time,
Kaposi's sarcoma and Pneumocystis carinii pneumonia were less common as AIDS-defining illness, whereas conditions associated with
more advanced immunosuppression became more common.
Because the study ended in 1995, the effect of the new protease inhibitors had no
real influence on the data. Dr Phillips estimates that only a "tiny portion" of the cohort had been treated with saquinavir in 1995,
and he plans to continue to monitor mortality trends in the AIDS patients seen at the Royal Hospital and to assess the impact
of treatment with protease inhibitors. Although studies of AIDS patients treated with these new drugs have yet to be completed,
he has already observed that the hospital's AIDS ward "...is quieter than it has been for this time of year."
Ref: BMJ 1997;314:00-00.
Source: Aegis
A California group found no significant differences in cognitive function between
asymptomatic HIV-positive and HIV-negative homosexual and bisexual men. They believe these results suggest that "...extreme caution
be exercised in assigning cognitive deficits to HIV asymptomatic individuals when there is a possibility that the observed decrement
is possibly caused by factors not accounted for by the research methods."
Dr. Diane L. Damos of UCLA and colleagues explain in the current issue of Archives
of Neurology that HIV is detectable in cerebrospinal fluid soon after seroconversion, which supports the possibility of cognitive
decline beginning during the asymptomatic phase of infection.
The investigators compared 27 educated HIV-positive asymptomatic men with 29 closely
matched controls. All subjects underwent extensive neuropsychological tests. Dr. Damos found that, "...unlike the results of
many other studies examining cognitive decrements in asymptomatic individuals, we found no significant differences on any of the
neuropsychological or information processing measures."
Dr. Damos also reports that "...computerised tests were not more sensitive to subtle
cognitive deficits than neuropsychological assessment ."
Ref: Arch Neurol 1997;54:179-185
Source: Aegis
The three chemokine co-receptors known to be involved in HIV-1 infection--CCR5, CXCR4,
and CCR3--are found in various types of cells and tissues. Resistance to HIV-1 infection has been linked to defective CCR5
alleles, suggesting that CCR5 plays an important role in HIV-replication in the body. In the central nervous system (CNS), HIV-1
targets brain cells known as microglia and causes AIDS-related dementia. Researchers now report that these target cells express
both CCR3 and CCR5. The researchers found that the CCR3 ligand, eotaxin, and an anti-CCR3 antibody inhibited HIV-1 infection
in the brain cells, as did a CCR5 ligand. The authors suggest that both co-receptors promote HIV-1 infection of the CNS and that
the identification of CCR3's role in the infection of microglia may lead to new treatments for AIDS-related dementia.
Ref: Nature (02/13/97) Vol. 385, No. 6617, P. 645; He, Jianglin; Chen, Youzhi; Farzan,
Michael; et al.
Source: Aegis
Researchers from the Pasteur Institute in Paris report that they have identified the
B cell superantigen-binding site of HIV-1 gp120. They believe the new finding may be important in the design of an effective
gp120-based HIV-1 vaccine.
Drs. Saoussen Karray and Moncef Zouali comment that, "[b]ecause of its strong immunogenicity
and its binding to CD4, the viral coreceptor, gp120 is considered a potential subunit vaccine candidate against this
virus." However, earlier research findings indicate that the "...gp120 envelope protein of HIV-1 is able to crosslink membrane IgM
on normal human B cells and to induce their activation in a VH3 immunoglobulin gene-family-specific manner." This superantigen
property "...is thought to have deleterious consequences for the host, including a progressive decline of B cells with progression
of the HIV-1 induced disease."
The investigators report that the B-cell superantigen-binding site "...is formed by
protein sequences from two regions of the gp120 molecule," and that it is present on highly divergent isolates of HIV-1. They
suggest that potentially deleterious superantigen effects "...might be offset by the use of a gp120 vaccine devoid of its superantigen-binding
site."
Ref: Proc Natl Acad Sci USA 1997;94:1356-1360.
Source: Aegis
HIV-infected infants who exhibit early CD8 viral suppressive activity appear to have
a slower rate of disease progression, according to a report in the January issue of AIDS.
Dr. Henry Pollack of NYU Medical Center and colleagues investigated the role and development
of CD8+ T-cell-mediated suppression of HIV replication in a cohort of vertically infected infants. Dr. Pollack noted
that during their first year of life, 11 of 16 infants had evidence of CD8 viral suppressive activity, which they defined as "...a
50% or greater reduction in p24 antigen in the cultures containing CD8+ cells."
He found that the children who had strong suppressive activity had a more favourable
early clinical outcome, as measured by survival and higher CD4 percentage at 1 year of life. The children showing CD8 viral suppressive
activity also had lower early peaks and 6-month "set-points" of plasma HIV RNA compared with the children who did not
exhibit suppressive activity.
There were no rapid progressors among the subjects with CD8 viral suppressive activity,
but the majority of subjects with no signs of suppressive activity had a rapid course of disease progression and died within
30 months of age.
Dr. Pollack concludes that a large proportion of HIV-positive infants exhibit CD8+
T-cell-mediated viral suppressive activity during early infection. This "...immune response appears to play an important protective
role in the early control of perinatal HIV infection at a time when other immune responses are either absent or deficient."
Ref: AIDS 1997;11:F9-F13.
Source: Aegis
For HIV-positive patients who still have relatively high CD4 cell counts, a multicentre
team reports that plasma virus RNA is the most useful marker of antiviral activity of a candidate therapeutic intervention.
Dr. Lawrence Corey of the University of Washington in Seattle and colleagues performed
detailed analyses for 29 untreated HIV-positive subjects with more than 600 CD4 cells/microliter and for 15 zidovudine-treated
HIV-positive subjects with between 400 and 550 CD4 cells/microliter. The investigators measured infectious HIV-1, proviral,
and virion RNA, on a monthly basis for an average of 11 months, along with CD4 and CD8 cell counts, in peripheral blood of the subjects.
Dr. Corey's group, reporting for the National Institute of Allergy and Infectious
Diseases AIDS Vaccine Evaluation Group, found that among subjects with similar CD4 cell counts, HIV-1 replication varied widely.
However, "...within-individual variability was significantly less that the variability between subjects for all virologic measures."
In particular, plasma virion HIV-1 RNA levels had the lowest intrapatient variability.
When the investigators devised a mathematical model designed to assess the effects
of potential therapy on viral load, they found that "...three measurements of plasma RNA would be outside the 95th percentile for
the expected change in an individual due to natural variability."
Overall, Dr. Corey concludes that "...this approach can be used to accurately assess
a therapeutic intervention among persons with low plasma HIV-1 titers."
Ref: J Infect Dis 1997;175:247-254.
Source: Aegis
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Data is accumulating that using HIV RNA to monitor therapy optimises patient management
and represents a cost-effective tool. Clinics failing to offer viral load testing as part of HIV care can no longer be seen
as providing an acceptable standard of care for persons with HIV.
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