DOCTOR FAX
ISSUE 3 24th July 1996
Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle,
Chelsea & Westminster Hospital.
Contents
XI International Conference on AIDS Special Issue
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STANDARDS OF CARE
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International AIDS Society (IAS) Issues Guidelines for Antiretroviral Therapy in Clinical Practice
Satellite Symposium - 10/07/96 Vancouver
IMPORTANT ADVANCES in understanding the biology and treatment of human immunodeficiency
virus (HIV) infection have occurred during the past 18 months. As a result, new scientifically sound approaches to therapy
have been developed that offer new options for persons with HIV infection. The relevant recent advances fall into 4 major categories:
(1) a better understanding of the replication kinetics of HIV throughout all stages of disease; (2) the development of assays
to determine the viral load in individual patients; (3) the availability of several new effective drugs; and (4) the demonstration
that combination therapy is more effective than zidovudine monotherapy.
In light of these advances, the recommendations of earlier state-of-the-art guidelines
are no longer applicable to clinical decision making in 1996. Therefore, an international panel of clinical investigators experienced
in HIV patient care was selected and convened by the International AIDS Society-USA to develop current recommendations
for the clinical management of HIV-infected individuals.
The panel addressed 4 central questions about antiretroviral therapy: when to initiate
therapy, which types of drugs to use, when to change therapy, and which types of drugs to use when a change in therapy is indicated.
In addition, the treatment of primary HIV infection, prevention of vertical transmission, and post-exposure prophylaxis
were addressed. The recommendations are not solely based on the results of controlled clinical trials with well-defined clinical
endpoints. Developing clinical guidelines in the HIV field at this time requires an approach firmly anchored in data from controlled,
double-blind clinical trials when available, but must also include information from trials in progress and available virologic
and immunologic endpoint data, as well as extrapolations from studies of the pathophysiology of HIV infection. Clinical
decisions must be made for best use of up to 8 available antiretroviral drugs, at a time when long-term studies with clinical endpoints
have been completed for only a few possible combinations.
When to Initiate Therapy
Ideally, therapy of HIV infection should be initiated before irreversible immunologic
damage has occurred. The decision of when to initiate therapy should be based on the assessment of disease progression risk.
Natural history studies and treatment trials demonstrate a continuum of increased risk with higher viral load and lower CD4+ cell count. As such, the experts differ somewhat with regard to the precise trigger
point for recommending therapy.
Recommendations for When to Initiate Treatment
| Status | Recommendation |
| Symptomatic HIV disease* | Therapy recommended for all patients |
| Asymptomatic, CD4+ cell count <0.500x109/L | Therapy recommended** |
| Asymptomatic, CD4+ cell count >0.500x109/L | Therapy recommended
for patients with
>30 000-50 000 HIV
RNA copies/mL or
rapidly declining CD4+
cell counts
Therapy should be
considered for patients
with >5000-10 000 HIV
RNA copies/mL |
*Symptomatic HIV disease includes symptoms such as recurrent mucosal candidiasis,
oral hairy leukoplakia, and chronic and unexplained fever, night sweats, and weight loss.
**Some would defer therapy in a subset of patients with stable CD4+ cell counts between 0.350 and 0.500 x 109/L and plasma HIV RNA levels consistently below 5000 - 10 000 copies/mL.
Clinical trial data support the initiation of therapy in patients with CD4+ cell counts below 0.500x109/L (or a CD4+ percentage of <25). Some experts would defer therapy in a subset of patients with
stable CD4+ cell counts between 0.350 and 0.500x109/L (eg, counts that remain at the same level for 18 to 36 months) in whom plasma HIV
RNA levels are consistently less than 5,000 to 10,000 HIV RNA copies/mL.
Available clinical trial results do not define the optimal treatment strategy for
asymptomatic patients with CD4+ cell counts above 0.500x109/L. In such patients, treatment is recommended for those with more than 30,000 to
50,000 HIV RNA copies/mL or with rapidly declining CD4+ cell counts (ie, a greater than 0.300x109/L loss over 12 to 18 months), based on the very high progression risk. Treatment
should be considered for patients with HIV RNA levels higher than 5,000 to 10,000 copies/mL based on the high progression risk.
However, any decision to initiate therapy at CD4+ cell counts above 0.500x109/L must be tempered by the fact that there are no available clinical data to support
treatment at this stage of HIV disease, and that such earlier therapy carries with it potential problems related to long-term
toxicity, tolerance, acceptance, expense, and the possible selection of drug-resistant virus.
Antiretroviral therapy should be initiated in all patients with symptomatic HIV disease
(eg, recurrent mucosal candidiasis; oral hairy leukoplakia; chronic or otherwise unexplained fever, night sweats, or weight
loss).
Initial Antiretroviral Regimens
A central question in the choice of an initial antiretroviral regimen is whether to
use the most potent antiretroviral therapy available first in all patients or to reserve such therapy for patients with a higher
pre-treatment progression risk or for those progressing after initial therapy has been instituted. At this time, both approaches
are defensible. Based on current virologic and immunologic data, the most potent treatment regimen at this time would probably
include 2 nucleoside analogues and a potent protease inhibitor; however, experience with protease inhibitors as initial therapy
and in early HIV disease is still limited. Until longer-term clinical trial data from initial regimens with protease inhibitors
are available, most patients in whom therapy is indicated should probably begin with 1 of the nucleoside analogue-containing
regimens described below.
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On the other hand it is important to keep in mind that if starting a potentially suboptimal regimen of a 2 drug nucleoside analogue combination you may run the risk of inadequate viral suppression. This can encourage
the subsequent development of drug resistant HIV, limiting future treatment options with obvious public health implications. |
The nucleoside analogue combinations with the most demonstrated clinical benefits
are zidovudine/didanosine and zidovudine/zalcitabine Zidovudine/lamivudine may be better tolerated and appears to have comparable
antiretroviral potency, but supporting clinical endpoint data are not now available. Also, there is some concern that initial
lamivudine therapy with resulting resistance mutations at reverse transcriptase codon 184 may impair later response to didanosine
or zalcitabine, should they be required.
Recommendations for Initial Therapy Regimens
Zidovudine/didanosine, or
zidovudine/zalcitabine,
or
zidovudine/lamivudine, or
didanosine monotherapy* | If a protease inhibitor is added to a nucleoside analogue-containing regimen, the
choice of protease inhibitor should be based primarily on antiretroviral potency and on other considerations as described in the
text.**;
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*Didanosine monotherapy may be less effective as initial therapy in patients with
more advanced HIV disease. Other possible non-zidovudine containing regimens include didanosine/stavudine, stavudine/lamivudine,
and stavudine monotherapy, although these regimens are less well studied.
**Antiretroviral potency refers to plasma HIV RNA and CD4+ cell count responses associated with these drugs at approved doses and with currently
available formulations.
Although emerging data support combination therapy, didanosine monotherapy is also
a reasonable option, particularly for patients who cannot tolerate or who refuse zidovudine. This approach may allow the possibility
of adding zidovudine at a later time or switching to zidovudine/zalcitabine or zidovudine/lamivudine, although there are no
published data regarding the efficacy of these regimens in patients previously treated with didanosine monotherapy.
Initial therapy with other non-zidovudine-containing combinations are less well supported
by clinical trial data. Stavudine/didanosine has antiretroviral potency that appears comparable to other 2-drug combinations;
careful monitoring is clearly indicated for neurotoxicity, especially in more advanced disease. Stavudine/lamivudine is well
tolerated, particularly for patients with limited bone marrow reserve who are poor candidates for zidovudine-containing regimens.
However, no formal evaluation of the pharmacokinetics, safety, or activity of the combination has been completed. Stavudine
monotherapy is also well tolerated, but available information does not permit adequate comparisons with other initial monotherapies
(zidovudine or didanosine). Zalcitabine and lamivudine are not satisfactory single-drug therapies.
| Encouraging data is now steadily accruing which indicates that non-ZDV containing
combination regimens show equal (if not enhanced) efficacy with reduced/different patterns of toxicity which may well suit individual
patients tolerance and/or preference.
|
As noted, it may be reasonable to include a protease inhibitor in the initial regimen
for any patient in whom therapy is indicated, particularly for patients at higher risk for progression. In this strategy, a
protease inhibitor could be added for symptomatic patients, patients with lower or rapidly falling CD4+ cell counts, and those with high plasma HIV RNA levels. The choice of a protease
inhibitor should be made on the basis of efficacy and potency, safety and tolerability, durability of antiviral effects, drug resistance
patterns, the potential for limiting future treatment options, and cost. Saquinavir, the first approved protease inhibitor,
is well tolerated but has limited bioavailability and thus potency in its currently available formulation. A new formulation
with improved bioavailability is under study. Indinavir is very potent and well tolerated. Toxic effects include benign hyperbilirubinemia
and a 3% to 4% rate of nephrolithiasis (stones are primarily composed of precipitated indinavir). Ritonavir is comparable
in potency to indinavir; it has more frequent adverse effects including gastrointestinal disturbance (20% to 25% of patients),
hepatotoxicity, headache, and transient circumoral paresthesia. Ritonavir is a particularly efficient inhibitor of the hepatic
enzyme cytochrome P450, which complicates its use with other drugs metabolised by this pathway. This may be particularly difficult
in patients with advanced HIV disease in whom 1 or more of these drugs are commonly required.
| Licensing of protease inhibitors for use in the UK - ritonavir expected date 15th August 1996, indinavir and saquinavir end October 1996. |
CHANGING ANTIRETROVIRAL THERAPY
Reasons for Changing Therapy
The initial antiretroviral regimen is of critical importance; however, few patients
will remain on that treatment for prolonged periods of time. In general, there are 3 primary reasons for considering a change
in antiretroviral therapy:
1. Treatment failure. Increased viral replication, due at least in part to the emergence
of drug-resistant viral variants, is directly linked to immunologic and clinical progression. Treatment failure is indicated
by increases in viral load (eg, a return toward or within 0.3 to 0.5 log10 of pre-treatment plasma HIV RNA levels), decreases in CD4+ cell count or percentage, or clinical progression. Ideally the patient should be
monitored frequently enough that the decision to change the regimen can be made before symptomatic disease progression occurs.
Plasma HIV RNA assays have provided precise and compelling data on the relative magnitude
and durability of effects of antiretroviral regimens. These data underscore the potential of plasma viral load levels, in
conjunction with CD4+ cell counts, for guiding treatment decisions. Preliminary guidelines are available
for using plasma HIV RNA levels in individual patient management. If used, plasma HIV RNA level should be measured 3 to 4 weeks
after initiating or changing therapy, and then periodically on the same schedule as CD4+ cell counts (eg, every 3 to 6 months). The minimum reduction in HIV RNA titre indicative
of antiretroviral activity is 0.5 log10 or more (about 3-fold) from pre-treatment value (based on intra-assay variability
of about 0.2 log10 and biologic variation of about 0.3 log10). The HIV RNA levels measured within about 1 month after immunisations or active
intercurrent illnesses may show substantial but transient elevations associated with these events, which will resolve without alteration
in therapy.
Some Selected Options for Changing Therapy Owing to Treatment Failure or Drug Intolerance*
|
Initial Regimen | Subsequent Regimen Options |
| Treatment Failure |
| Zidovudine* | Zidovudine/didanosine protease inhibitor
Zidovudine/lamivudine protease inhibitor
Didanosine protease inhibitor
Didanosine/stavudine protease inhibitor |
| Didanosine | Zidovudine/lamivudine protease inhibitor
Zidovudine/didanosine protease inhibitor
Stavudine/protease inhibitor |
| Zidovudine/didanosine | Zidovudine/lamivudine protease inhibitor
Stavudine/protease inhibitor |
| Zidovudine/zalcitabine | Zidovudine/lamivudine protease inhibitor
Stavudine/protease inhibitor
Didanosine/protease inhibitor |
| Zidovudine/lamivudine | Didanosine/protease inhibitor
Stavudine/protease inhibitor
Didanosine/stavudine
Lamivudine/stavudine |
Drug Intolerance
| Zidovudine* | Didanosine
Didanosine/stavudine
Lamivudine/stavudine
Stavudine |
| Didanosine | Zidovudine/lamivudine
Lamivudine/stavudine
Stavudine/protease inhibitor |
Zidovudine/zalcitabine
Intolerance to zidovudine
| Didanosine
Didanosine/protease inhibitor
Didanosine/stavudine
stavudine/protease inhibitor |
| Intolerance to zalcitabine Zidovudine/lamivudine
| Zidovudine/lamivudine protease inhibitor
Didanosine/protease inhibitor
Stavudine/protease inhibitor
Didanosine/stavudine |
*For patients whose initial regimen includes a protease inhibitor, subsequent regimens
should include at least 2 new drugs chosen from among nucleoside analogues, nonnucleoside reverse transcriptase inhibitors,
and protease inhibitors (one should be selected for which there is likely to be little or no cross-resistance to the initial protease
inhibitor).
ÜConsidered a suboptimal regimen; all patients on zidovudine monotherapy should be
re-evaluated.
áA protease inhibitor could be added to the nucleoside analogue regimens listed.
|
Given the recent clinical endpoint data on the combination of ddC (zalcitabine) +
Saquinavir showing prolongation of life and delays in disease progression, ddC + protease inhibitor should be included in the above
options. |
The occurrence of HIV-associated clinical complications is considered evidence of
treatment failure. The goal of using virologic and immunologic parameters to guide therapy is to prevent clinical disease progression,
as clinical indicators of progression are, at best, insensitive and late indicators of treatment failure. Decisions to change
treatment are often made relatively late, perhaps in part because of limited options and access to drugs, the general conservatism
of many physicians, and the implication that altering therapy acknowledges disease progression. However, accumulating evidence
suggests that earlier decisions to change therapy are more likely to have a significant impact on disease progression.
CD4+ cell enumeration has been extensively used to guide treatment decisions. As with
plasma HIV RNA measurements, it is not possible to strictly define CD4+ cell changes that definitely indicate that a change in therapy should be made. Most
experts would view a return of CD4+ cell counts to pre-treatment values as evidence of a loss of drug effect. Other factors,
such as rate of decline of CD4+ cell count and extent to which additional treatment regimens are available, should
also be considered.
2. Toxicity, intolerance, or non-adherence. Each of the available antiretroviral treatments
is associated with dose-limiting toxic effects. In general, they occur more frequently in individuals with advanced disease;
in addition, overlapping toxicitys with other drugs are more likely to encroach on therapeutic options in patient populations
with more advanced disease. Physicians and patients must maintain an open dialogue about toxic effects and adherence
to drug regimens.
3. Current use of a suboptimal treatment regimen. Zidovudine monotherapy is a suboptimal
regimen and treatment should be re-evaluated in any patient who is receiving it.
Considerations for Stopping Antiretroviral Therapy
Stopping antiretroviral therapy may be appropriate in patients with very advanced
disease for whom there are significant toxicity and quality-of-life issues associated with continued antiretroviral therapy. Data
on viral dynamics support the need for continuous therapy with continued monitoring and reevaluation of the antiretroviral regimen.
The consequences of drug withdrawal are immediately evident (within days) in terms of increases in plasma HIV RNA levels.
In light of this, efforts should be made to manage drug-related toxicity before all therapy is abandoned.
Source: Journal of the American Medical Association, July 10, 1996. Vol 276, No.2.
and oral satellite presentation, Vancouver - 10/07/96
(Editorial comments in italics)
The next issue of the ATP doctor fax will include the IAS guidelines for primary infection,
post-exposure prophylaxis, and recommendations for vertical transmission prophylaxis.
We would strongly recommend to clinicians the fully referenced text of these guidelines,
the source of which is given above.
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ATP would like to reinforce the concern expressed by many conference delegates at
the conservatism of these guidelines concerning triple combinations including a protease inhibitor - both when initiating and changing
therapy. Clinicians at the forefront of HIV care already consider triple therapy the standard of care, and this is now reimbursed
as such in some European countries Ie.Holland.
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OPPORTUNISTIC ILLNESSES
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Clinical Variables Predict PCP
A study presented today demonstrated that clinical variables can accurately predict
Pneumocystis carinii pneumonia (PCP) in HIV-infected patients. The finding suggests that HIV-infected patients with suspected
PCP may be spared the expense of definitive diagnostic tests and, in the case of bronchoscopy, invasive diagnostic procedures.
Table: Clinical variables associated with PCP
(bivariate analysis)
|
Variable | Odds ratio | p-Value |
| CD4+ cell count < 50 cells/mm3 | 2.32 | 0.027 |
| PCP prophylaxis | 0.46 | 0.025 |
| Absence of purulent sputum | 9.60 | 0.001 |
| Serum LDH > 220 U/L | 3.57 | 0.03 |
| Chest x-ray with granular | 30.4 | <0.0001 |
| opacities | 5 | |
| O2 saturation <93% | 2.79 | 0.002 |
The study group included 164 HIV-infected patients with suspected PCP. All patients
underwent clinical evaluation and laboratory studies including chest radiography, and all patients without a confirmed diagnosis
of PCP were followed for 60 days to assess for the subsequent development of PCP.
As reported by Laurence Huang and colleagues of San Francisco General Hospital, PCP
was definitively diagnosed in 60 patients (37%). A number of clinical variables were associated with PCP in bivariate analysis
(See table). In multivariate analysis, the strongest independent predictors of PCP were a chest radiograph (x-ray) with granular
opacities, CD4+ cell count < 50 cells/mm3, and absence of purulent sputum. None of the patients with purulent sputum and a chest
x-ray without granular opacities had PCP. The researchers concluded that PCP is unlikely in HIV-infected patients with purulent
sputum without granular opacities on chest x-ray, and that diagnostic testing for PCP in such patients may be unwarranted.
Source: AIDScan, July 10, 1996.
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PCP
Unknown serostatus thwarts prevention
Pneumocystis carinii pneumonia (PCP) remains the most frequent AIDS-defining opportunistic
infection in the US.
In a session yesterday, Laurence Huang of San Francisco General Hospital presented
results of a multivariate analysis designed to determine which patients will need to undergo bronchoscopy -- an invasive, uncomfortable
and expensive procedure. Huang's team has shown that predictors of PCP are a chest radiograph with granular opacities,
a CD4+ cell count of less than 50 per microlitre and the absence of purulent sputum.
Avoidance of bronchoscopy was also the focus of a presentation by Elena Angeli of
Milan. For those who cannot tolerate the procedure, the potential for using serum blood samples instead is under active investigation.
There does appear to be a correlation between acute PCP and the presence of DNA in the serum, Angeli said, although it is
rapidly cleared following treatment. "It is a fragile and fragmented molecule so the collection and processing needs to be rapid,"
she stressed.
In the preventive area, Markus Flepp of the University Hospital in Zurich described
a study of patients treated for PCP which found that 32% had been unaware of their HIV status at the time they presented with
their first episode.
Lack of prophylaxis for PCP is also an issue in parts of the US. Jeff Duchin of the
University of Washington suggested that a large proportion of initial episodes of PCP in the Seattle area may be due to delayed
diagnosis of HIV. Even when HIV status is confirmed as positive, PCP prophylaxis is often not initiated or compliance is poor.
Source: Guenther Krueger. The Daily Progress, 10/07/96.
With advances in antiretroviral combination therapy, and the obvious advantages of
opportunistic infection prophylaxis, is it now time to reassess the need for a pro-testing campaign for HIV in at-risk populations
in the UK?
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OBSTETRICS
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Efforts Target Prevention of Perinatal HIV Transmission
Knowledge of the risk factors associated with perinatal HIV transmission continues
to expand at a steady pace, but the identification of optimal prevention strategies remains elusive. While the overwhelming need
for effective treatment regimens for acute and chronic HIV infection may have shifted attention away from the problem of perinatal
HIV transmission in the past, experts warn that this can no longer be permitted.
"As the number of women who become HIV-infected continues to increase, perinatal infection
will also increase," said Yvonne Bryson, MD, Director of the Los Angeles Pediatric AIDS Consortium. "This will soon be
a major global problem."
The statistics by now are well known. The World Health Organisation estimates that
by the year 2000, five to ten million children will have been infected with HIV, with the vast majority by vertical transmission.
Transmission rates in untreated women vary by population and geographic area, with a low of about 13% reported by the European
Collaborative Study to a high of nearly 40% documented in early studies in Africa.
Speaking at a plenary session, Bryson noted that current evidence suggests that perinatal
HIV transmission occurs in utero, during labour and delivery, and by breast feeding. About half of HIV-infected infants
have positive virus cultures at birth, while the remaining half are culture-negative and presumed to have acquired HIV during the
intrapartum period. Bryson said that maternal HIV transmission is multifactorial, and that a variety of potential factors affecting
perinatal HIV transmission have been documented.
Potential factors influencing perinatal HIV transmission
- Mode of delivery
- Duration of labour
- CD4+ cell count
- Use of invasive procedures
- Cervical viral shedding
- Prolonged duration of ruptured membranes
- Length of gestation
- Neutralising antibody
- Breast feeding
- HIV plasma RNA levels
- Multiple births
- Placental pathology
Intrapartum Transmission
A growing body of evidence supports intrapartum transmission as one of the major routes
of acquisition of perinatal HIV infection, Bryson said. The belief is supported by recent findings indicating a decreased
risk of vertical transmission among infants born by Caesarean delivery and an increased risk among those with exposure to maternal
blood during delivery and those born more than four hours following rupture of the amniotic membranes. As the role of intrapartum
transmission in perinatal HIV infection becomes increasingly apparent, investigators have focused on the characteristics of
labour and delivery and other perinatal factors that may influence the risk of perinatal HIV transmission.
The role of the second stage of labour on the risk of vertical HIV transmission was
examined in a study by L. Normand and colleagues of Montreal. The prospective study involved 97 pregnant women, of whom 16 received
ZDV during pregnancy. Information on demographic, behavioural, immunologic, virologic, clinical, and intrapartum events was
collected during pregnancy and delivery, and HIV infection in infants was confirmed by two positive HIV cultures.
The overall rate of vertical HIV transmission was 25.7%, and the risk of vertical
HIV transmission was significantly lower among women treated with ZDV (6.25%) than among untreated women (29.6%). After controlling
for ZDV use, the mean duration of the second stage of labour was significantly associated with HIV transmission. The mean duration
of the second stage of labour was significantly longer in HIV-infected infants (66.5 minutes) than among non-infected infants
(16.7 minutes). The effect of labour duration on the risk of vertical HIV transmission was significant in multiparous (p =
0.04) but not among primiparous (p = 0.14) women. The researchers speculated that prolonged contact with cervical and vaginal secretions
during delivery increases the risk of perinatal acquisition of HIV.
Placental membrane inflammation was associated with a significantly increased risk
of vertical HIV transmission in a study by F. Wabwire-Mangen and colleagues of Uganda. The study group included 171 HIV-infected
women enrolled at 28 weeks of gestation and followed through delivery. After delivery, the placentas of all women were examined
grossly and histopathologically. Vertical HIV transmission was defined as having HIV antibody at 15 months of age or a positive
HIV PCR assay at six months.
Of the 171 HIV-positive women, 41 (24%) transmitted HIV vertically and 130 (76%) were
nontransmitters. The placental membrane inflammation types, funisitis and chorioamnionitis, were associated with a significantly
increased risk of vertical HIV transmission (relative risk, 2.49 and 3.58, respectively). In contrast, no increased risk was
observed in women with any placental villous inflammation types or gross placental abnormalities.
Maternal HIV RNA Levels
Bryson noted that a growing body of evidence suggests that HIV RNA levels during pregnancy
can influence the risk of vertical transmission of HIV, and that high maternal virus load is a critical risk factor associated
with vertical HIV transmission. Little is known, however, about the effects of pregnancy on maternal plasma RNA levels.
In a study by D. Burns and colleagues of the National Institutes of Health, HIV RNA
levels were measured in plasma samples obtained from 138 HIV-infected pregnant women prior to the third trimester, during the
third trimester, and two months postpartum. Only six women received antiretroviral therapy during pregnancy (of whom two transmitted
HIV perinatally).
There was little overall change in the HIV RNA copy number between the period prior
to the third trimester, the period during the third trimester, and the postpartum period, the researchers reported. There was,
however, a strong overall association between the HIV RNA copy number during the third trimester and vertical transmission of HIV,
and the association was independent of CD4+ cell count and the duration of ruptured membranes.
The effect of maternal HIV RNA load at delivery on the risk of perinatal HIV transmission
was examined by D. Thea and colleagues of New York in a study of 105 HIV-infected pregnant women and their infants. Of the
105 women, 51 gave birth to HIV-infected infants and 54 were nontransmitters.
HIV RNA levels were measured in all women in plasma obtained eight weeks prior to
delivery and two weeks post-delivery. The geometric mean HIV RNA load was significantly higher in transmitters (15,300 copies/mL)
than in nontransmitters (7200 copies/mL), and the vertical transmission rate was significantly lower among women with undetectable
HIV RNA (22%) than among those with HIV RNA levels in the highest quartile (65%). Women with HIV RNA levels above the limit
of detection were significantly more likely to transmit HIV perinatally than were women with undetectable HIV RNA.
Prevention
Findings from such trials raise further questions regarding the optimal approach to
the prevention of vertical HIV transmission. In the "landmark" perinatal HIV prevention trial, ACTG 076, ZDV initiated in the
second or third trimester and continued during labour reduced the risk of maternal HIV transmission from 25% to 8.3%. Bryson speculated
that the mechanism of protection of ZDV may be reduction of the maternal viral load and a possible protective effect on
the foetus. The efficacy of other ZDV monotherapy regimens, and the benefits of ZDV in combination with other antiretroviral agents,
remains unknown.
Efficacy of preventive interventions may vary according to the timing of initiation,
CD4+ cell count, HIV RNA levels, and other variables, Bryson said, and the goals of future preventive measures should include
maximum lowering of the maternal viral load. Studies of newer approaches to the prevention of perinatal HIV transmission, either
planned or underway, include the use of combination antiviral regimens, immunoglobulins, monoclonal antibodies, vaginal washing,
vitamin A supplementation, and vaccines administered to the mother, infant, or both.
Source: AIDScan, July 10, 1996.
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IMMUNOLOGY
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Distinguished lecturers debate chemokines, drug convenience
The pace of HIV replication -- and hence viral load over time -- is governed by a
complex network of interactions among a variety of factors, some produced by the host and some by the virus. Anthony S. Fauci of
the National Institute of Allergy and Infectious Disease in the US elaborated on the current state of knowledge regarding these
crucial mechanisms. The most important of the host factors are the endogenous cytokines, which tightly control viral expression.
Potent inducers of HIV replication include TNFalpha, IL-1beta and IL-6, which, said
Fauci, are overexpressed in the lymphoid tissues of HIV-positive individuals. Blocking these factors also blocks their action
to increase viral load.
Suppressors of viral replication -- at least in certain kinds of laboratory cultures
-- include the beta-chemokines RANTES, MIP-1alpha and MIP-1beta. These factors are produced by many cells of the immune system,
including monocytes, B-cells and CD4+ and CD8+ T-cells. But things are not quite so simple, Fauci said. In other kinds of cultures
such as a CD4+-dendritic cell co-culture tested by Fauci and his colleagues, and
described in another Tuesday session by Andrea Rubbert -- beta-chemokines cannot account for the full extent of observed viral suppression.
Hence, the existence of other T-cell factors has been posited which are active under certain conditions, said Fauci.
Overall, the further elucidation of these complex mechanisms offers rich opportunities for further research.
Jay Levy of the University of Californias Cancer Research Institute emphasised the complexity of the pathways involved in
these host factors. Levy said that the action of a CD8+ cell antiviral factor (CAF), distinct from the beta-chemokines, may play
a role in the continued health of long-term survivors.
The final speaker in this session was Paul Volberding, director of the AIDS program
at San Francisco General Hospital. He stressed that scientific advances must be accompanied by a more patient-friendly approach
on the part of drug designers and physicians. What is needed, he said, is "expert, patient-oriented care" that combines "high
technology with compassion."
In short, said Volberding, potency is not the only consideration in effective drug
design. "We have to make convenience a priority. Drugs should not interfere with other necessary treatments. Drugs should be able
to be taken not more than twice daily and should not require fasting in order to be absorbed."
Source: The Daily Progress, 11/07/96.
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MEDICINES EVALUATION
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AIDS Treatment Project Executive Director Raffi Babakhanian Addresses Key Plenary
Session at Vancouver Conference
European AIDS activists on Thursday appealed to the European Commission to speed up
its drug approval process, accusing bureaucrats of killing people with delays.
Organisers of the 11th International Conference on AIDS invited the European AIDS
Treatment Group on stage to make an appeal directly through the conference's main plenary session.
"The European Commission has no sense of urgency with regards to getting new AIDS
drugs to patients," said Raffi Babakhanian of the European AIDS Treatment Group.
He directly addressed Irish Health minister of state Brian O'Shea, whose country currently
holds the rotating European Union presidency. O'Shea chairs the EU Council of Health Ministers.
"Mr O'Shea, I am asking you to pick up the phone and tell the Commission to get its
act together," Babakhanian said. "Because killing time is killing people."
Babakhanian complained that AIDS drugs such as 3TC (Glaxo Wellcome's Epivir), Indinavir
(Merck's Crixivan), saquinavir (Hoffman-LaRoche's Invirase) and ritonavir (Abbott Laboratories' Norvir) had all been approved
by the European Medicines Evaluation Agency (EMEA) in London, but that the Commission had not given final approval.
The drugs have been found to suppress the HIV virus when used in a combination therapy.
The EU has 90 days to act on EMEA recommendations.
Source: Reuters NewMedia, Inc.
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