New Data Indicates Zidovudine Does Not Reduce Incidence of KS
US guidelines updated
The US Public Health Service issued an updated draft on 5th November of its Guidelines
for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. The Guidelines were first published in June 1997
(see ATPs Doctor Fax Issue 26), with a request for comments from the public. According to
one of the authors, Gabriel Torres MD, the panel received 179 written submissions in response to the draft, which have been taken
into consideration in the latest version. The final recommendations are expected to be published in January, but will remain subject
to regular updates.
The Guidelines, in addition to those issued for the use of antiretrovirals during
pregnancy and in children, can be accessed on the internet in standard HTML format at:
http://www.healthcg.com
PDF format of these documents can be found at:
http://www.hivatis.org
There have been minor changes and modifications through the Guidelines and this feature
lists all the substantive differences from the previously published draft.
Viral load monitoring
The new draft recommends viral load monitoring every 3-4 months among untreated people,
while the previous draft suggested 3-6 monthly monitoring.
After treatment is initiated, the updated Guidelines suggest that viral load should
be checked after 4-8 weeks to ensure that there has been an adequate fall, whereas previously a timepoint of 4 weeks was recommended.
Since the summer, there has been growing interest in new tests that can measure viral
load that is lower than the current limit of detection (around 400 to 500 copies/ml). The Roche Ultrasensitive assay, for example,
having a lower limit of detection of 50 copies/ml. The new Guidelines address these tests, noting:
As more sensitive assays are developed, the level of detectability will undoubtedly
be lower; however, the significance of suppression even beyond the current recommended level, given the variability of test results
at the lower limits of detectability, is unknown."
[See DocFax 35 and this issue, however, for insights gained from long-term suppression
studies on the durability of response and lack of resistance achieved by suppressing below 20 copies/ml]
The recommendation that treatment decisions should be based on two viral load tests,
taken closely together, still stands. However, the Guidelines now also note:
"However, in patients who present with advanced HIV disease, antiretroviral therapy
should generally be initiated after the first viral load measurement is obtained in order to prevent a potentially deleterious
delay in treatment. In addition, it is recognised that the requirement for two measurements of viral load may place a significant
financial burden on patients or payers. Nonetheless, the Panel feels that two measurements of viral load will provide the clinician
with the best information for subsequent follow-up of the patient."
Finally, the use of viral load in assessing an individual's likely risk of disease
progression has been recalculated. Previous estimates of the risk of progression at specific levels had been adjusted to take account
of the possibility that some of the virus in the stored samples might have been lost. However, more recent research has found
that very little viral RNA is likely to have been lost in the stored samples. Overall, the estimated risk of disease progression
for an individual with a certain viral load is likely to have increased.
Starting treatment
The list of recommended regimens for people starting treatment has now been extended
to take account of studies of the combination of saquinavir and ritonavir. The panel note that this combination, without any
additional drugs such as nucleoside analogues (also known as NRTIs: namely AZT, ddI, ddC, 3TC or d4T), "appears to be potent in
suppressing viraemia below detectable levels, and has convenient BID [twice daily] dosing". However, they also note that the safety
of the combination "has not been fully established", and it has not formally been compared to triple combinations consisting
of two NRTIs plus a protease inhibitor (PI). For the time being, then, the panel recommends that "at least one additional NRTI
be used when the physician elects to use 2 PIs as initial therapy".
The panel now also address the differences between the two U.S. licensed NNRTI drugs,
nevirapine and delavirdine (available in Europe on compassionate use programmes). The Guidelines suggest that nevirapine should
normally be used in preference to delavirdine, because of the former's superior effects on viral load.
In an addition to this section, the new draft states:
"When initiating antiretroviral therapy, all drugs should be started simultaneously
at full dose with the following three exceptions: dose escalation regimens are recommended for ritonavir, nevirapine, and in some
cases, ritonavir plus saquinavir."
Finally, the tables on Drug Interactions Between Protease Inhibitors And Other Drugs
and Drug Interactions Between Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors have been updated and expanded.
Changing therapy
The recommendation for changing therapy if the viral load reduction is inadequate
has been changed slightly. It now suggests changing therapy if there reads "change therapy if there has been less than a 0.5-0.75
log reduction in plasma HIV RNA by 4 weeks following initiation of therapy, or less than a 1 log reduction by 8 weeks".
The Guidelines now give more detailed recommendations for people who have achieved
undetectable viral load on a treatment regimen consisting only of two NRTIs alone detailing the reduced durability compared to
achieving undetectable on a 3-drug regimen. They argue:
"Patients currently receiving 2 NRTIs who have achieved the goal of no detectable
virus have the option of continuing this regimen or may have modification to conform to regimens in the preferred category (Table
VI). Prior experience indicates that most of these patients on double nucleoside therapy will eventually have virologic failure
with a frequency that is substantially greater compared to patients treated with the preferred regimens."
An expanded list of recommended regimens for people who started treatment on two NRTIs
now suggests:
The new draft contains a fuller discussion of the likelihood of a successful response
to a new regimen among people for whom a triple therapy regimen has failed, stating:
"At present there are very few clinical data to support specific strategies for changing
therapy in patients who have failed the preferred regimens that include PIs; however, a number of theoretical considerations
should guide decisions. Because of the relatively rapid mutability of HIV, viral strains with resistance to one or more agents
often emerge during therapy, particularly when viral replication has not been maximally suppressed. Of major concern is recent
evidence of broad cross-resistance among the class of PIs. It appears that viral strains that become resistant to one PI will
have reduced susceptibility to most or all other PIs. Thus, the likelihood of success of a subsequently administered PI + 2 NRTI
regimen, even if all drugs are different from the initial regimen, may be limited, and many experts would include 2 new PIs in
the subsequent regimen."
In the light of new data, the combination of nelfinavir and saquinavir plus two new
NRTIs is now a recommended salvage option for people experiencing treatment failure with two NRTIs plus either ritonavir or indinavir.
An entirely new section now addresses Considerations for Antiretroviral Therapy in
the HIV-Infected Adolescent, which suggests that those infected sexually or via injecting drug use may have a different disease
course than those infected perinatally or via blood products, and makes recommendations for dosing regimens during puberty.
Treatment during pregnancy
An expanded section on the use of anti-HIV drugs during pregnancy -- a subject covered
in detail in a separate set of draft guidelines -- now notes that diabetes can be a complication of pregnancy in some cases,
and it is not yet known whether protease inhibitors (which can themselves cause or exacerbate diabetes) increase this risk.
The Guidelines now contain a fuller discussion of the pros and cons of prescribing
AZT monotherapy to reduce the risk of mother-to-baby transmission among pregnant women whose own condition would not normally merit
anti-HIV therapy -- for example, those with a CD4 count greater than 500 and viral load below 10,000 to 20,000. They explain
that the risk of developing resistance is probably lessened by the low level of HIV replication in such individuals, and their
relatively short period of exposure to monotherapy in the second and third trimesters of pregnancy. However, "for women with more
advanced disease and/or higher levels of HIV RNA, concerns about resistance are greater and they should be counselled that a
combination antiretroviral regimen that includes ZDV for reducing transmission risk would be more optimal for their own health than
use of ZDV chemoprophylaxis alone".
Seroconversion illness
Finally, this latest draft of the Guidelines now includes estimates of the frequency
of various symptoms during primary HIV infection (also known as seroconversion illness).
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Table VI. Recommended Antiretroviral Agents for Treatment of Established HIV Infection
Preferred
: Strong evidence of clinical benefit and/ or sustained suppression of plasma viral
load (2,33,34)
One choice each from column A and column B*. Drugs are listed in random, not priority,
order:
Column A
|
Column B
|
|
Indinavir (AI) | ZDV + ddI (AI) |
|
Nelfinavir (AII) | d4T + ddI (AII) |
|
Ritonavir (AI) | ZDV + ddC (AI) |
|
Ritonavir + Saquinavir (BII) | ZDV + 3TC# (AI) |
|
| d4T + 3TC# (AII) |
Allternative: Less likely to provide sustained virus suppression (35)
1 NNRTI (Nevirapine)** + 2 NRTIs (Column B, above) (BII)
Saquinavir (hard gel capsule) + 2 NRTIs (Column B, above) (BI)
Not generally recommended: Strong evidence of clinical benefit but initial virus suppression
is not sustained in most patients (36,37)
2 NRTIs (Column B, above) (CI)
Not recommended ##: Evidence against use, virologically undesirable, or overlapping
toxicities
All monotherapies (DI)
d4T + ZDV (DI)
ddC +ddI ### (DI)
ddC +d4T ### (DI)
ddC + 3TC (DI)
* The current hard gel capsule formulation of saquinavir is not recommended as first
line therapy due to poor bioavailability. New formulations developed to increase the bioavailability of saquinavir are currently
under study. When using saquinavir + ritonavir, one or two NRTIs should also be used (38,39).
** The only combination of 2 NRTIs + 1 NNRTI that has been shown to suppress viraemia
to undetectable levels in the majority of patients is ZDV+ddI+Nevirapine. This combination was studied in antiretroviral naive
individuals (35).
# High level resistance to 3TC develops within 2-4 weeks in partially suppressive
regimens; optimal use is in 3 drug antiretroviral combinations that reduce viral load to <500 copies/ml.
## ZDV monotherapy may be considered for prophylactic use in pregnant women with low
viral load and high CD4 T cell counts to prevent perinatal transmission, as discussed under "Considerations in the Pregnant Woman."
###This combination of NRTIs is not recommended based on lack of clinical data using
the combination and/or overlapping toxicities.
Rating Scheme for Clinical Practice Recommendations
Strength of Recommendation
A: Strong, should always be offered
B: Moderate, should always be offered
C: Optional
D: Should generally not be offered
E: Should never be offered
Quality of Evidence
I: At least one randomised trial with clinical endpoints
II: Clinical trials with laboratory endpoints
III: Expert opinion
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Table XIII. Guidelines for Changing an Antiretroviral Regimen for Suspected Drug Failure
-
Criteria for changing therapy include a suboptimal reduction in plasma viraemia after
initiation of therapy, re-appearance of viraemia after suppression to undetectable, significant increases in plasma viraemia
from the nadir of suppression, and declining CD4 T cell numbers. Please + refer to the more extensive discussion of these on page
10.
- When the decision to change therapy is based on viral load determination, it is preferable
to confirm with a second viral load test
- Distinguish between the need to change a regimen due to drug intolerance or inability
to comply with the regimen versus failure to achieve the goal of sustained viral suppression; single agents can be changed or
dose reduced in the event of drug intolerance.
- In general, do not change a single drug or add a single drug to a failing regimen;
it is important to use at least two new drugs and preferably to use an entirely new regimen with at least three new drugs.
- Many patients have limited options for new regimens of desired potency; in some of
these cases it is rational to continue the prior regimen if partial viral suppression was achieved.
- In some cases, regimens identified as sub-optimal for initial therapy are rational
due to limitations imposed by toxicity, intolerance or non-adherence. This especially applies in late stage disease. For patients
with no rational alternative options who have virologic failure with return of viral load to baseline (pretreatment levels) and
a declining CD4 T cell count, there + should be consideration for discontinuation of antiretroviral therapy.
- Experience is limited with regimens using combinations of two protease inhibitors
or combinations of protease inhibitors with nevirapine or delavirdine; for patients with limited options due to drug intolerance
or suspected resistance these regimens provide possible alternative treatment options.
- There is limited information about the value of restarting a drug that the patient
has previously received. The experience with zidovudine is that resistant strains are often replaced with "wild-type" zidovudine
sensitive strains when zidovudine treatment is stopped, but resistance recurs rapidly if zidovudine is restarted. While there
is preliminary evidence that this occurs with indinavir, it is not known if similar problems apply to other nucleoside analogues,
protease inhibitors, or NNRTIs, but a conservative stance is that they probably do.
- Avoid changing from ritonavir to indinavir or vice versa for drug failure, since high
level cross resistance is likely.
- Avoid changing from nevirapine to delavirdine or vice versa for drug failure, since
high level cross-resistance is likely
- The decision to change therapy and the choice of a new regimen requires that the clinician
have considerable expertise in the care of people living with HIV. Physicians who are less experienced in the care of persons
with HIV infection are strongly encouraged to obtain assistance through consultation with or referral to a clinician with
considerable expertise in the care of HIV-infected patients.
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Table XII. Drug Interactions: Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors
Drug Affected | Indinavir | Ritonavir | Saquinavir | Nelfinavir | Nevirapine | Delavirdine |
Indinavir
(IDV)
|
* | No data | Levels: IDV no effect; SQV 4-7x
Dose: no data | Levels IDV 50%; NFV 80%
Dose: no data | Levels IDV 10-30%
Dose: IDV 1000mg tid. | Levels: IDV 40%
Dose: IDV 600mg q8h
|
Ritonavir
(RTV) |
No data
|
* | Levels: RTV no effect; SQV 20x
Dose: SQV 400mg bid + RTV 400mg bid | Levels: RTV no effect; NFV 1.5x
Dose: no data. | Levels: RTV 11%
Dose: Standard | Levels: RTV and DLV levels unchanged; standard doses not studied
Dose: no data
|
Saquinavir
(SQV) |
Levels: SQV 4-7x; IDV no effect
Dose: no data | Levels: SQV 20x; RTV no effect
Dose: SQV 400mg bid + RTV 400mg bid
|
* | Levels: SQV 3-5; NFV 20% (This study used the unlicensed SQV soft gel cap)
Dose: Standard (No dose adjustment needed with hard gel formulation) | Levels: SQV 25%
Avoid use | Levels: SQV 5x
Dose: Standard (monitor transaminase levels)
|
Nelfinavir
(NFV) |
Levels: NFV 80%; IDV 50%
Dose: no data | Levels: NFV 1.5x; RTV no effect
Dose: no data | Levels: NFV 20%; SQV 3-5x (This study used the unlicensed SQV soft gel cap)
Dose: Standard (No dose adjustment needed with hard gel formulation)
|
* | No data
Some experts use NFV 1000mg tid + NVP 200mg bid | Levels: NFV 2x; DLV 50%
Dose: Standard (monitor for neutropaenia first few months) |
Nevirapine
(NVP) |
Levels: IDV 10-30%
Dose: IDV 1000mg tid | Levels: RTV 11%
Dose: Standard | Levels: SQV 25%
Avoid use | No data
Some experts use NFV 1000mg tid + NVP 200mg bid
|
* | No data |
Delavirdine
(DLV) |
Levels IDV 40%
Dose: IDV 600mg q8h | Levels RTV and DLV levels unchanged; standard doses not studied
Dose: Standard | Levels SQV 5x
Dose: Standard | Levels: NFV 2x; DLV 50%
Dose: Standard (monitor for neutropaenia) | no data
|
* |
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Table XIX. Possible Regimens For Patients Who Have Failed
Antiretroviral Therapy: A Work in Progress.#
Prior Regimen New Regimen (Not listed in priority Order) |
2 NRTIs +
| 2 new NRTIs +
|
Nelfinavir
| RTV or IDV or SQV +RTV or NNRTI## +
RTV or NNRTI + IDV**
|
Ritonavir
|
SQV + RTV , NFV + NNRTI or NFV + SQV
|
Indinavir
|
SQV + RTV, NFV +NNRTI or NFV + SQV
|
Saquinavir
| RTV + SQV or NNRTI +IDV
|
2 NRTIs + NNRTI
| 2 New NRTIs + protease inhibitor
|
2 NRTIs
| 2 New NRTIs + protease inhibitor
2 New NRTIs + RTV +SQV
1 New NRTI + 1 NNRTI + protease inhibitor
2 protease inhibitors + NNRTI
|
1 NRTI
| 2 New NRTIs + protease inhibitor
2 New NRTIs + NNRTI
1 New NRTI + 1 NNRTI + protease inhibitor
| |
These alternative regimens have not been proven to be clinically effetive and were
arrived at through discussion by the panel of theoretically possible alternative treatments and the elimination of those alternatives
with evidence of being ineffective. Clinical trials in this area are urgently needed.
# RTV = ritonavir, IDV = indinavir, SQV = saquinavir, NVP = nevirapine, NFV = nelfinavir,
DLV = delavridine
** There are some clinical trials with viral burden data to support this recommendation
## Of the two available NNRTIs, clinical trials support a preference for nevirapine
over delavirdine based on results of viral load assays. These two agents have opposite effects on the CYP 450 pathway and this
must be considered in combining these drugs with other agents.
The above tables are reproduced from the full document to which you should refer for
the references.
Update report sources:
aids.miningco.com / Crix-List. Authors: Edward King / Bob Munk
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|
ANTIVIRALS
|
Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral
therapy
As reported in the last issue of the Doctor Fax, Faucis group were due to report their eradication data in the forthcoming issue of PNAS. Faucis study complements the studies published in Science covered in Doctor Fax Issue 35.
ABSTRACT
: Although highly active antiretroviral therapy (HAART) in the form of triple combinations
of drugs including protease inhibitors can reduce the plasma viral load of some HIV-1-infected individuals to undetectable
levels, it is unclear what the effects of these regimens are on latently infected CD4+ T cells and what role these cells play
in the persistence of HIV-1 infection in individuals receiving such treatment. The present study demonstrates that highly purified
CD4+ T cells from 13 of 13 patients receiving HAART with an average treatment time of 10 months and with undetectable (<500
copies HIV RNA/ml) plasma viraemia by a commonly used bDNA assay carried integrated proviral DNA and were capable of producing
infectious virus upon cellular activation in vitro. Phenotypic analysis of HIV-1 produced by activation of latently infected CD4+
T cells revealed the presence in some patients of syncytium-inducing virus. In addition, the presence of unintegrated HIV-1 DNA
in infected resting CD4+ T cells from patients receiving HAART, even those with undetectable plasma viraemia, suggests persistent
active virus replication in vivo.
Ref: Chun T-W, Stuyver L, Mizell SB, Ehler LA, Mican JM, Baseler M, Lloyd AL, Nowak
MA, Fauci AS. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci.
USA 94:13193-13197 (Nov 25, 1997)
The science papers commented on in the last issue of Doctor Fax carried out similar
investigations to the Fauci group but in subjects who had achieved less than 50 copies/ml plasma HIV RNA over considerably longer
periods (up to 3 years). It has to be emphasised that the patients in Faucis group had less than 500 copies/ml, but we dont know how much less, and had only an average of 10 months treatment. This may explain
why active replication was found in this study, but was apparently absent in the Science studies (as measured by lack of genetic
change in inducible HIV RNA after up to 3 years of treatment).
This tells us that measuring to less than 500 copies is inadequate to discriminate
between patients in which viral evolution is or is not likely to occur. Assays detecting below 50 copies/ml are much more likely
to inform us as to which patients are at risk of evolution of resistance (ie. those between 50 - 500 copies/ml).
|
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|
PATHOGENESIS
|
In Vivo Evolution of HIV-1 Co-Receptor Usage and Sensitivity to Chemokine-Mediated Suppression
Nine children perinatally infected with HIV-1 were studied to determine what inhibitive
effect the C-C chemokines RANTES, MIP-1 alpha, MIP-1 beta, and MCP-1 and the C-X-C chemokine SDF-1 have on HIV-1 infection.
At varying stages of HIV-1 infection in the children, the scientists obtained a total of 33 sequential primary viral isolates,
which they tested using a healthy donor's activated peripheral blood mononuclear cells. RANTES and MIP-1 beta were found to inhibit
all but two of the isolates recovered during early stages of the infection, and MIP-1 alpha was found to be effective with
most of those isolates. Combining the three chemokines together produced an additive HIV-suppressive effect, and MCP-1 had no
effect on the viral isolates. However, 60 percent of the viral isolates obtained from the children in later stages of infection
did not react to RANTES, MIP-1 alpha, or MIP-2 beta, suggesting their ability to use CXCR4 and sometimes CCR3 while slowly losing
CCR5 usage. The majority of the isolates were also insensitive to MCP-1. According to the researchers, the findings indicate
that HIV-1 undergoes an adaptive change in vivo, which helps it avoid the effects of the antiviral C-C chemokines.
Ref: Nature Medicine (11/97) Vol. 3, No. 11, P. 1259; Scarlatti, Gabriella; Tresoldi,
Eleonora; Bjorndal, Asa; et al.
Source: CDC NCHSTP Daily News Update.
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Thymus Scan Study
Dr. Mike McCune and the thymus study team of the Gladstone Institute of Virology and
Immunology in San Francisco held a community forum on September 24 to present the results of their recently completed thymus
scan study.
A total of 99 HIV-positive and 33 HIV-negative volunteers participated in this project
and received thymus CT scans over the past year. A draft of the paper describing the full study, their results, and their conclusions
is being submitted to a medical journal.
In brief, the study turned up a surprising finding: it appears that functioning thymus
in not only present in HIV-positive adults, but that its function may actually be enhanced is some adults. There are two patterns
in the data that point in this direction. First, out of all of the HIV-positive volunteers (and especially in those 34 years
of age or younger), moderate or high thymus mass (scores of 3 or 4) was found most frequently in those with CD4+ cell counts
in the mid-range (300-500 cells/mm3). HIV-positive volunteers with counts above 500, surprisingly, actually were less likely to
have abundant thymus compared to those volunteers who had experienced some disease progression. Volunteers with counts below 300
were also less likely to have high thymus masses compared to those people with mid-range counts.
The second interesting result was that, among volunteers over the age of 40, none
(0/10) of those who were HIV-negative had high thymus mass, whereas high thymus mass was found in some of the HIV-positive volunteers.
Thymus scores of 3 or better were found in 26% (9/34) of HIV-positive participants with CD4+ cell counts of 500 or below,
and 50% (95/10) of those whose CD4+ cell counts were over 500.
Source: "Whats New", Oct 97. A service of Project Inform.
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New Data Indicates Zidovudine Does Not Reduce Incidence of KS
Researchers report in the November issue of Clinical Infectious Diseases that use
of zidovudine does not appear to lower incidence of Kaposis sarcoma. Although previous clinical studies indicated that the drug could lower
the incidence by about 33 percent, Dr. Marshall M. Joffe of the University of Pennsylvania School of Medicine and colleagues said
those studies could have been limited by low statistical power and heterogeneity, with the positive data the result of chance.
Joffes team used data collected in the Multicenter AIDS Cohort Study of nearly 5,000 men.
Source: CDC NCHSTP Daily News Update.
Although it now looks unlikely that ZDV alone directly lowers incidence of KS, triple
therapy with a protease inhibitor with or without ZDV is strongly associated with a reduction in the incidence of KS. This argues
for an immunological mechanism (ie. restoration of immune competence), and not a substance specific effect of antiretrovirals
|
Thank you to all those who sent letters of support after the request in the last Doctor
Fax. Anyone who has not yet managed, but would like to send a letter of support is still most welcome to do so.
These letters will help ATP in its fundraising activities. AIDS Treatment Project does not currently receive statutory
funding.
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