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NEW TREATMENT GUIDELINES
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The U.S. Public Health Service on June 20 released a draft of new guidelines for treatment
of HIV infection in adults, accompanied by a statement of principles for treatment that should help explain the guidelines,
and also help clinicians adapt the guidelines as new drugs become available. Each of these forty-page documents was prepared
by a panel of experts and community representatives. There is now a 30-day period for public comment on the guidelines, before
they are revised (if necessary) and printed as a special supplement to the Centers for Disease Control's weekly newsletter, MMWR
(Morbidity and Mortality Weekly Reports).
An attractive aspect of these guidelines is that they offer flexibility for individual
assessment and patient and physician choice. The document recognises that experts continue to disagree on some key points,
such as exactly when in the course of infection to start therapy. In cases of disagreement, the panel presents its best consensus
or dominant opinion but also clearly explains the difference of opinion and evidence for each viewpoint.
The consensus on what therapy is best, whenever it is started, is quite clear: a three
drug regimen containing a potent protease inhibitor (PI) (meaning indinavir, ritonavir or nelfinavir but not the currently
available formulation of saquinavir alone) and one of the following recommended combinations of nucleoside analogues (NAs): d4T plus ddI, ZDV plus ddI, ZDV plus ddC, ZDV plus 3TC, and d4T plus 3TC.
It cautions that for the two options containing 3TC, it is critically important that
the combination as a whole suppresses viral load to undetectable (less than 500 copies per ml) levels or else resistance to 3TC
is likely to develop within a very short time, two to four weeks.
The following NA combinations should not be used together in any combination due to
overlapping toxicitys and/or in-vitro antagonism: ZDV plus d4T, ddC plus ddI, ddC plus d4T, and ddC plus
3TC. It also strongly recommends against any monotherapy (using only one antiviral of whatever type). Also listed as "not generally
recommended" are combinations of two NAs only such as those used in the Delta and CAESAR studies.
The following summaries and comments are extracted from the two documents.
The Panel strongly believes that new antiretroviral drugs and treatment strategies,
if used correctly, can be of great benefit to HIV-infected persons. However, as our understanding of HIV disease has improved
and the number of available beneficial therapies has increased, clinical care of HIV-infected patients has become much more complex.
Therapeutic success increasingly depends on a thorough understanding of the pathogenesis of HIV disease and on familiarity
with when and how to use the more numerous and more effective drugs available to treat HIV infection. The Panel is concerned that
even these new potent antiretroviral therapies will be of little clinical utility for treated patients unless they are used correctly,
and that, used incorrectly, they may even compromise the potential to obtain long-term benefit from other antiretroviral
therapies in the future.
This is the second, complimentary, document which uses the context of these 11 principles
to produce a pathogenesis-based rationale for therapeutic strategies and practical guidelines to their implementation.
The following tables are contained in the full document:
I. Rating Scheme for Clinical Practice Recommendations
II. Indications for Plasma HIV RNA Testing
III. Risks and Benefits of Early Initiation of Antiretroviral Therapy in the Asymptomatic
HIV-Infected Patient
IV. Multicenter AIDS Cohort Study (MACS): Disease Progression Rates by CD4 and Viral Load
Category
V. Indications for the Initiation of Antiretroviral Therapy in the Chronically HIV-Infected
Patient
VI. Recommended Antiretroviral Agents for Treatment of Established HIV Infection
VII. Characteristics of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
VIII. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
IX. Characteristics of Protease Inhibitors
X. Drugs That Should Not Be Used With Protease Inhibitors
XI. Drug Interactions Between Protease Inhibitors And Other Drugs
XII. Drug Interactions: Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors
XIII. Guidelines for Changing an Antiretroviral Regimen for Suspected Drug Failure
XIV. Suggested New Regimens for Patients Who Have Failed Antiretroviral Therapy
XV. Acute Retroviral Syndrome: Associated Signs and Symptoms
XVI. Preclinical and Clincal Data Relevant to Use of Antiretrovirals in Pregnancy
The selected tables which follow are extracted from this second document.
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Table III. Risks and Benefits of Early Initiation of Antiretroviral Therapy in the Asymptomatic HIV-Infected Patient
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Table II. Indications for Plasma HIV RNA Testing
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Clinical Indication | Information | Use |
| Syndrome consistent with acute HIV infection | Establishes diagnosis when HIV antibody test is negative or indeterminate | Diagnosis |
| Initial evaluation of newly diagnosed HIV infection | Baseline viral load "set point" | Decision to start or defer therapy |
| Every 3-4 months in pts. not on therapy | Changes in viral load | Decision to start therapy |
| 4 weeks after initiation of antiretroviral therapy | Initial assessment of drug efficacy | Decision to continue or change therapy |
| 3-4 months after start of therapy | Maximal effect of therapy | Decision to continue or change therapy |
| Every 3-4 months in pts. on therapy | Durability of anti-retroviral effect | Decision to continue or change therapy |
| Clinical event or decline in CD4+ T cells | Association with changing or stable viral load | Decision to continue, initiate, or change therapy |
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Table V. Indications for the Initiation of Antiretroviral Therapy in the Chronically HIV-Infected Patient
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Clinical Category | CD4+ T Cell Count and HIV RNA | Recommendation |
| Symptomatic (AIDS, thrush, unexplained fever) | Any value | Treat |
| Asymptomatic | CD4+ T Cells <500/mm3 orHIV RNA >10,000 (bDNA) or >20,000 (RT-PCR) | Treatment should be offered. Strength of recommendation is based on prognosis for disease-free survival as shown in Table IV and willingness of the patient to accept therapy.* |
| Asymptomatic | CD4+ T Cells >500/mm 3 andHIV RNA <10,000 (bDNA) or <20,000 (RT-PCR) | Some experts would delay therapy and observe; however, some experts would treat |
* Some experts would observe patients with CD4+ T cell counts between 350-500/mm3 and
HIV RNA levels <10,000 (bDNA) or <20,000 (RT-PCR).
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Table VI. Recommended Antiretroviral Agents for Treatment of Established HIV Infection
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Column A | Column B |
| Indinavir | ZDV + ddI |
| Nelfinavir | d4T + ddI |
| Ritonavir | ZDV + ddC |
| ZDV + 3TC# | |
| d4T + 3TC# |
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Table XIV. Suggested New Regimens for Patients Who Have Failed Antiretroviral Therapy*#
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Prior Regimen | New Regimen (Not listed in priority order) |
| 2 NRTIs + | 2 new NRTIs + |
| Nelfinavir | Rit; or Ind; or Saq + Rit; or Nev + Rit; or Nev + Ind** |
| Ritonavir | Saq + Rit or Nel + Nev ** |
| Indinavir | Saq + Rit or Nel + Nev |
| Saquinavir | Nel; or Rit; or Rit + Saq; or Nev + Ind |
| 2 NRTIs + Nevirapine | 2 new NRTIs + a protease inhibitor |
| 2 NRTIs | 2 new NRTIs + a protease inhibitor |
| 1 NRTI | 2 new NRTIs + a protease inhibitor 2 new NRTIs + nevirapine |
* These suggested alternative regimens have not been proven to be clinically effective.
** There are some clinical trials with surrogate marker data to support this recommendation
# Rit = ritonavir, Ind = indinavir, Saq = saquinavir, Nev = nevirapine, Nel = nelfinavir
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Table XIII. Guidelines for Changing an Antiretroviral Regimen for Suspected Drug Failure
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These new US guidelines will almost certainly now be viewed as the current gold-standard for the therapy of HIV-infection. The principles of treatment - achieving a plasma
viral load as low as possible, preferably undetectable are essentially the same as in the BHIVA guidelines. When this is translated into
a practical approach, however, the US guidelines are much more forthright about the necessity for a maximally suppressive, aggressive
approach up-front. Once a decision to start treatment has been made, the US guidelines argue clearly that the first combination
to be used should, in almost all cases, be 2NAs + a potent protease inhibitor. The exclusion of saquinavir from the options for first line protease inhibitor use may seem strange to British physicians who have been schooled in the idea that it is a well-tolerated drug which, even if resistance arises, will leave future options open for switching to the other available PIs. There is, however, a vigorous and rational voice amongst both physicians and US treatment activists, which argues that saquinavir, in its currently licensed formulation (hard gelatin capsule) is suboptimal and should never have been licensed at the currently recommended dose of 600 mg q8h. They also assert that at the time of licensing, a maximally tolerated dose for saquinavir had not been determined and evidence was already in existence for the increased potency in vivo of doses twice as high, with equal tolerability. Concern over the possibilities for inadequate viral suppression, resistance and cross-resistance with such a sub-optimal dose may have been borne out by the interim results of ACTG 333 (see ATPs DocFax Issue 20). The later development of a three-times more bioavailable formulation (saquinavir soft gel capsule) and its use by Roche in current studies at twice the dose of the current formulation echos these public concerns. Roche has recently presented exciting data on saquinavir SGC to both European and US activists. ATP strongly supports swift regulatory approval of the new formulation which will clearly have an important place in future treatment regimens. For further background on the dispute over the development and use of saquinavir see: http://www.aidsnyc.org/tag/sqv.html Regarding viral load testing, Table 2 suggests use of a 4 week viral load to assess response for decision to change. However, the BHIVA document recommends 3 months after commencement or change of therapy. In a range of studies three months represents the nadir response and in the saquinavir + ritonavir study was predictive of viral load at week 24. Anecdotal observations have also been made that it may take up to six months for viral load to fall below detectable. Premature testing at week 4, with an expectation of undetectable, may both disappoint recipients and prompt discontinuation of an effective regimen, thus discarding treatment options. Next months issue of NAMs AIDS Treatment Update will examine British Doctors responses to the new US guidelines. |
A 13-member panel of the International AIDS Society (USA) has updated recommendations
for antiretroviral therapy in HIV-infected patients made public last summer at the International AIDS Conference in Vancouver.
The revised guidelines, which appear in the June 25th issue of the Journal of the American Medical Association, follow close
on the heels of similar guidelines released by the National Institutes of Health (see previous article).
In its recommendations made at Vancouver, the IAS panel suggested treatment be initiated
in patients with viral loads greater than 30,000 copies/ml regardless of CD4+ count and clinical state, and in patients with
viral loads of 5,000 to 10,000 copies/ml whose CD4+ count or clinical condition indicated disease progression. However, the
updated guidelines call for treatment to begin in patients with more than 5,000 copies/ml regardless of the number of CD4+ cells.
As in the NIH guidelines, triple combination therapy is strongly recommended as the
most powerful approach, preferably with a combination of two nucleoside analogues and one protease inhibitor. As well, both documents
insist that rising viral loads be viewed as evidence of treatment failure and cause for replacing at least two of the drugs
in question. Finally, each set of guidelines stresses the importance of dialogue between physician and patient to ensure that
a firm commitment to compliance is made before treatment begins; in other words, is the patient willing and able to take his or
her drugs as directed?
Consensus Statement - June 25, 1997
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ANTIVIRALS
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Results released on the largest ever AIDS study show conclusively that a three-drug
therapy including the protease inhibitor saquinavir is clinically significantly superior to a standard two-drug regimen.
Combining saquinavir with ddC plus ZDV delayed disease progression and prolonged survival
in patients without or limited prior anti-retroviral therapy by 50 per cent (p=0.0001) compared to patients starting therapy
with ddC plus ZDV alone.
Dr Graeme Moyle, Associate Director of HIV research at Chelsea and Westminster Hospital,
London and a SV- 14604 investigator said: "This study shows the dramatic benefit of combining saquinavir with ddC and ZDV
- a 50% reduction in the onset of AIDS. This is the first study to demonstrate the value of including a protease inhibitor, such
as saquinavir, in a standard double nucleoside analogue regimen in previously untreated patients.
Commenting on the study, Dr Hans J rgen Stellbrink, from the German University Hospital Hamburg-Eppendorf, and study
investigator concluded, "Until recently, many physicians have reserved protease inhibitors for patients with advanced disease.
The study data now confirms that the combination of saquinavir and two nucleoside analogues show remarkable effect on previously
untreated patients and establish it as a first-line option in the management of previously untreated HIV infection."
In the clinical study SV-14604, a total of 3,485 patients participated from 22 countries.
The trial started in August 1994 and lasted until January 1997. Patients who used a triple combination of saquinavir,
ddC and ZDV experienced a total of 76 clinical endpoints (first AIDS defining event or death) compared with 142 clinical endpoints
in patients receiving ddC and ZDV alone. Results from this clinical trial will be submitted to the regulatory authorities in
order to update the product labelling for saquinavir.
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This study is a watershed study, rather like Delta was for the end of monotherapy.
This larger study confirms the clinical advantage of starting with triple therapy including a protease inhibitor which should mark
the end of initial double nucleoside analogue combination prescribing. The initial ZDV monotherapy group did not perform as well as initial triple therapy suggesting treatment intensification approaches may not be as effective as 3 drugs up-front. These results are even more impressive when concerns about the potency of saquinavir are taken into account. One wonders how they might compare to initial triple combination therapy including the US guideline recommended potent protease inhibitors indinavir, ritonavir or nelfinavir? This was a moderately advanced population (mean CD4 count 200 cells/mm3) and even though the benefit of triple therapy was highly significant, the progression rate to AIDS or death was still 8% in the triple therapy arm. Interestingly, surrogate marker (CD4 and viral load) changes were not reported in the executive summary, fuelling speculation that they may not be as impressive as those seen with other protease inhibitor containing triple combinations. Analysis of the correlation between surrogate marker changes and clinical events in this study are eagerly awaited. Despite low bioavailability, saquinavir is 2 -3 times more active in vitro than ritonavir or indinavir and has a good tolerability profile, a fact probably rflected in these results. If the reformulated soft gel capsule saquinavir can indeed deliver useful blood levels of the drug, even more impressive results than those seen in this SV 14604 study might be seen. |
Initial therapy using zidovudine (ZDV) combined with either lamivudine (3TC) or didanosine
(ddI) is far more effective at staving off disease progression or death in children with symptomatic HIV disease than using
ddI alone, according to a large multicentre study supported by the National Institutes of Health (NIH).
Preliminary results of the study, which was terminated early, indicate that combination
antiretroviral therapy should be the preferred initial treatment for symptomatic HIV-infected children, particularly those
under 3 years of age, who have never been treated with anti-HIV drugs.
"These results provide new hope for young children who develop symptomatic HIV disease.
The preliminary results of this study clearly demonstrate that combination therapy can significantly slow disease progression
and reduce the risk of death in HIV-infected infants and children, as is the case in adults," says Anthony S. Fauci, M.D.,
director of the National Institute of Allergy and Infectious Diseases (NIAID), which supported the study along with the National
Institute of Child Health and Human Development (NICHD).
On June 18, 1997, an independent Data and Safety Monitoring Board (DSMB) reviewed
preliminary results of the study, known as AIDS Clinical Trials Group (ACTG) 300, and recommended that enrolment be stopped early
and that the study be closed. The DSMB based this recommendation on the obvious improvement in clinical benefits conferred by
the combination regimens over ddI monotherapy, which had been shown earlier to provide significant clinical benefits in a similar
population of children.
"The dramatic reduction in disease progression and death noted with the combination
regimens was most evident in the group under age 3," says Ross McKinney, M.D., of Duke University Medical Center in Durham, N.C.,
protocol chair of ACTG 300. He adds, "The findings increase the urgency to explore the effects in young children of more intensive
combinations that include protease inhibitors." Two protease inhibitors, nelfinavir and ritonavir, were recently approved
in the US for treating HIV-infected children.
A total of 615 infants and children participated in the study; data from 596 of them
were included in the preliminary analysis. These included 236 patients on ZDV/3TC, 235 on ddI monotherapy and 125 on ZDV/ddI.
Of the 596, 42 percent were male; 63 percent were black; 22 percent were Hispanic; 14 percent were white; and 1 percent were of
other ethnic origin.
ACTG 300, a randomised, double-blind Phase 2/3 study, opened in July 1995. It was
initially designed to determine the safety and efficacy of the three regimens of treatment in symptomatic HIV-infected infants
and children up to 15 years of age who had received little or no prior antiretroviral therapy. However, in February 1996, another
paediatric treatment trial, ACTG 152, found that ZDV/ddI and ddI alone conferred similar clinical benefit. Based on these results,
the ACTG 300 protocol team decided about a year ago to stop enrolment into the ZDV/ddI treatment arm.
Therefore, most of the analyses done on ACTG 300 to date have compared data from the
ZDV/3TC and the ddI monotherapy groups only. For their analyses, the investigators stratified the participants by age at entry
(less than 3 years or equal to or greater than 3 years) because younger children are at greater risk for developing a faster
course of HIV disease. About 20 percent of HIV-infected children develop serious disease in the first year of life; most of these
children die by age 4 years. Fifty-three percent of the ACTG 300 participants included in the data analysed were younger than
3 years old.
At enrolment, the patients ranged in age from 42 days and 15 years old. They had
symptomatic HIV disease based on criteria developed by the Centers for Disease Control and Prevention (CDC) and had received less
than 56 days of prior antiretroviral therapy. The overall median CD4+ T cell count was 728 cells per cubic millimetre (mm3) of blood.
The primary clinical outcomes of the study were disease progression and survival.
Disease progression was defined as worsening to CDC Category C classification (clinical AIDS-defining condition or abnormally low
CD4+ T cell count), inadequate growth, or deterioration in neurologic and neuropsychologic function.
Initially, children were assigned at random to receive either ZDV/3TC, ZDV/ddI or
ddI alone. Based on the results of ACTG 152, the protocol team stopped accruing patients into the ZDV/ddI arm in May 1996, and
new enrolees continued to be assigned to either of the other two treatment groups. However, children in all three arms remained
on blinded therapy and were followed for study outcomes.
The analyses of the data from children concurrently randomised to all three treatment
groups indicated that survival and delay in disease progression were significantly improved for the groups receiving either
combination when compared with those in the ddI monotherapy arm.
The two-arm analyses found that ZDV/3TC decreased the chance of disease progression,
including death, by 70 percent relative to ddI monotherapy. Growth failures and central nervous system deterioration were the
most common clinical endpoints reported. The differences between the two groups were primarily due to outcomes in the group of
children under age 3 years, where most endpoints (83 percent) and all the deaths (three on ZDV/3TC and 15 on ddI alone) occurred.
Only nine cases of disease progression occurred in the older group of patients, limiting the conclusions that can be drawn from
that study stratum.
The results also revealed differences in changes in CD4+ T cell counts between the
ZDV/3TC and ddI study arms from baseline to weeks 36-48. Children who received ZDV/3TC had a significantly greater increase in
absolute CD4+ T cell counts (median 73 cells/mm3) compared with the ddI treatment group (median 4 cells/mm3).
The investigators observed no major differences in the safety or toxicity of the three
treatment regimens except for a slight increase in hepatic toxicity in the patients who received ddI. In general, patients
tolerated the medications well.
Substudies of ACTG 300, including one evaluating HIV levels in the patients' blood
and another monitoring the development of drug resistance, are currently being analysed. Preliminary data suggest that all treatments
reduced viral load below baseline levels but that the combination regimens did so more effectively.
The findings from both ACTG 300 and ACTG 152 demonstrate that combination antiretroviral
therapy significantly slows disease progression and decreases mortality among children with HIV disease. The studies differ,
however, as to their conclusions regarding the relative clinical efficacy of ddI monotherapy compared with combination therapy.
Reasons for the difference between these two studies are not readily apparent but may be due in part to an increased rate
of early central nervous system (CNS) progression endpoints observed in the ddI monotherapy arm of ACTG 300. This might be related
to somewhat more sensitive measures used in ACTG 300 to assess CNS progression. In addition, ACTG 300 had a shorter average
length of follow-up compared with ACTG 152 (11 months versus 32 months). The protocol team has further analyses under way to better
understand the differences between the two studies.
Source: NIH
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The utility of three-drugs better than two is now evident from studies such as the saquinavir trial reported in this issue.
It is also the expected approach for any adult considering antiretroviral therapy for HIV-infection. Sadly paediatric drug development
lags behind, and only now is the change from monotherapy to dual producing its expected good results. The availability of
nelfinavir for children should help partially remedy this problem, and many physicians treating children at the cutting edge have
been using combinations including ritonavir since that drug received its paediatric indication in the US. |