TREATMENT ALERTS

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TREATMENT ALERT

ABACAVIR (ZIAGEN™)

Following the updated warning on abacavir from the US FDA the European Medicines Evaluation Agency (EMEA) has also issued a warning to European patients and physicians.

The warnings concern the potentially fatal hypersensitivity reaction to abacavir which occurs in approximately 5% of those taking this drug. It was known previously that restarting abacavir after experiencing symptoms of hypersensitivity could trigger and acute reaction which was potentially fatal. It was also known that hypersensitivity may be difficult to detect as many of the symptoms may mimic other common illnesses. This new warning, however, comes after reports of severe or fatal reactions occurring after abacavir was restarted in patients who had NO previous symptoms of hypersensitivity.

This means that there is the potential for anyone who was previously tolerating abacavir but who interrupted treatment for any reason to develop a life threatening reaction if they restart this drug. In some patients who developed hypersensitivity the reason for stopping abacavir was simply running out of the drug. In others abacavir was stopped during the treatment of other medical conditions.

The FDA updated warning on abacavir was reproduced in HTB Vol 1, No 5. The EMEA warning is reproduced below:

The European Agency for the Evaluation of Medical Products

Evaluation of Medicines for Human Use

London, 14 August 2000

EMEA/CPMP/23842/00

EMEA PUBLIC STATEMENT ON ZIAGEN (abacavir)

Abacavir hypersensitivity cases following an interruption of therapy

The following public statement contains essential information for anyone prescribing or taking Ziagen (abacavir)1.

The European Agency's for the Evaluation of Medicinal Products (EMEA) scientific committee, the Committee for Proprietary Medicinal Products (CPMP), has recently been made aware of new information related to serious hypersensitivity reactions associated with Ziagen (abacavir).

Hypersensitivity reactions (HSR) are a known concern with this product. These potentially serious reactions are usually characterised by the appearance of symptoms indicating multi-organ system involvement. Nearly all the patients with HSR experience fever or rash but symptoms may mimic other common gastrointestinal or respiratory diseases. These reactions usually occur within the first 6 weeks of treatment, but can occur at any time, and were the subject of an urgent safety restriction in January of this year (please see EMEA public statement EMEA/1952/00 dated 24th January 2000 for further information.)

Hypersensitivity reactions with rapid onset may occur when treatment with Ziagen is restarted in patients who were not previously diagnosed as having a hypersensitivity reaction. These patients typically had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. On very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction.

The EMEA wishes to draw attention to the following updated information on the management of hypersensitivity reactions to Ziagen:

As an urgent measure, the prescribing and patient information and the labelling have been modified through a rapid procedure at the request of the marketing authorisation holder. The EMEA thought it necessary to provide this new information to the public. Relevant changes to the product information are indicated below. For the complete scientific evaluation of Ziagen and the complete revised product information see the European Public Assessment Report, also available on the EMEA website.

For further information contact:

Mr Noel Wathion

Head of Sector Pharmacovigilance and Regulatory Affairs

Unit of Evaluation of Medicines for Human Use

Tel: + 44 207 418 85 92

Fax: + 44 207 418 8420

1Ziagen 300 mg film-coated tablets and 20 mg/ml oral solution contain abacavir, a nucleoside reverse transcriptase inhibitor, and were authorised in the EU on the 8th July 1999 for the antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus infected adults. Ziagen is marketed in Austria, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden and United Kingdom.

7 Westferry Circus,

Canary Wharf.

London

E14 4HB.

UK

Tel. (44-20) 74 18 84 00

Fax(44-20) 74 18 86 13

E-mail: mail@emea.eudra.org

http://www.eudra.org/emea.html

EMEA 2000 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged

PROVISIONAL CHANGES INTRODUCED

TO INFORMATION TO PRESCRIBERS

Ziagen 300 mg film-coated tablets as relevant example

 

INFORMATION TO PRESCRIBERS 4.4

Special warnings and special precautions for use

Hypersensitivity Reaction (see also 4.8 Undesirable effects):

In clinical studies approximately 4% of subjects receiving abacavir develop a hypersensitivity reaction; some of these cases were life threatening and resulted in a fatal outcome despite taking precautions.

Description

Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the syndrome.

Other signs and symptoms may include respiratory symptoms such as dyspnoea, sore throat, or cough, gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia).

The symptoms related to this hypersensitivillv reaction worsen with continued therapy and can be life threatening. These symptoms usually resolve upon discontinuation of Ziagen.

Management

Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Patients should be monitored closely, especially during the first two months of treatment with Ziagen, with consultation every two weeks.

Patients who are diagnosed with a hypersensitivity reaction whilst on therapy MUST discontinue Ziagen immediately.

Ziagen, or any other abacavir containing medicinal product, MUST NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death.

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Ziagen must be discontinued ifhypersensitivitj, cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). If reintroduction is judged necessary, it must be done in a hospital setting.

Special care is needed for those patients simultaneously starting treatment with Ziagen and other medicinal products known to induce skin toxicity (such as non nucleoside reverse transcriptase inhibitors). This is because it could be difficult to differentiate between rashes induced by these products and abacavir related hypersensitivity reactions

Management after an interruption of Ziagen therapy

If therapy with Ziagen has been discontinued for any reason and restarting therapy is under consideration, the reason for discontinuation must be established to assess whether the patient had any symptoms of a hypersensitivity reaction prior to stopping.

Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after re-starting Ziagen in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. On very rare occasions hypersensitivity reactions have been reported in patients who have re-started therapy, and who had no preceding symptoms of a hypersensitivity reaction. If a decision is made to re-start Ziagen this must be done in a setting where medical assistance is readily available.

Essential patient information

Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis have been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

Pancreatitis has been reported, but a causal relationship to Ziagen treatment is uncertain.

Insufficient data are available to recommend the use of Ziagen in children. In this population, hypersensitivity reactions are particularly difficult to identify.

Data to support the use of Ziagen in patients with moderate hepatic impairment are not currently available, therefore, administration of Ziagen should be avoided in these patients.

Ziagen should not be administered to patients with end-stage renal disease (see 5.2 Pharmacokinetic properties).

Patients receiving Ziagen or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Patients should be advised that current antiretroviral therapy, including Ziagen, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

4.8 Undesirable effects

Hypersensitivity (see also 4.4 Special warnings and special precautions for use):

In clinical studies, approximately 4% of subjects receiving abacavir developed a hypersensitivity reaction; some of these were life threatening and resulted in fatal outcome despite taking precautions. This reaction is characterised by the appearance of symptoms indicating multi-organ/body-system involvement.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever.

The signs and symptoms of this hypersensitivity reaction are listed below. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.

Skin:- Rash (usually maculopapular or urticarial)
Gastrointestinal tract:- Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration
Respiratory tract:- Dyspnoea, sore throat, cough
Miscellaneous:- Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis
Neurological/Psychiatry:- Headache, paraesthesia
Haematological:- Lymphopenia
Liver/pancreas:- Elevated liver function tests
Musculoskeletal:- Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase
Urology:- Elevated creatinine, renal failure

Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in diagnosis of hypersensitivity has resulted in Ziagen being continued or re-introduced, leading to more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases.

Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Close medical supervision is necessary during the first two months, with consultations every two weeks.

Risk factors that may predict the occurrence or severity of hypersensitivity to abacavir have not been identified. However, it is likely that intermittent therapy may increase the risk of developing sensitisation and therefore occurrence of clinically significant hypersensitivity reactions.

Consequently, patients should be advised of the importance of taking Ziagen regularly.

Restarting Ziagen following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction was usually more severe than on initial presentation, and may include life-threatening hypotension and death.

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Ziagen must be discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). If reintroduction is judged necessary it must be done in a hospital setting.

Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after re-starting Ziagen in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen. On very rare occasions hypersensitivity reactions have been reported in patients who have re-started therapy and who had no preceding symptoms of a hypersensitivity reaction. If a decision is made to restart Ziagen this must be done in a setting where medical assistance is readily available.

Each patient must be warned about this hypersensitivity reaction to abacavir.

For many of the other adverse events reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV disease or as a result of the disease process.

The following adverse reactions may be related to Ziagen. The majority of these have not been treatment limiting. Care however must be taken to eliminate the possibility of a hypersensitivity reaction if any of these symptoms occur.

Gastrointestinal: nausea, vomiting, diarrhoea Other: headache, fever, lethargy, fatigue, anorexia

Pancreatitis has been reported, but a causal relationship to Ziagen treatment is uncertain.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4 Special warnings and special precautions for use).

In controlled clinical studies laboratoty abnormalities related to Ziagen treatment were uncommon, with no differences in incidence observed between Ziagen treated patients and the control arms.

The full document, including INFORMATION TO PATIENTS and the ALERT CARD TEXT is available online at:

http://www.eudra.org/humandocs/PDFs/PS/2384200en.pdf

comment

Despite these new warnings it is still unclear what might constitute an interruption in treatment while on abacavir. It probably isn't missing one dose, but is it 2, 3 or more? Once that interruption has occurred, for whatever reason, treating physicians recommend admission to hospital for 2 - 3 days to monitor if abacavir is restarted.

Abacavir is contained in the Glaxo Wellcome drug Ziagen™ and as one of the three drugs contained in Trizivir™. These warnings apply equally to both Ziagen and Trizivir.

Unfortunately, although Trizivir would seem attractive for those who might experience adherence problems, this population may also be the most likely to interrupt and restart inadvertently.

Shockingly Glaxo Wellcome in response to press concerns over the safety of abacavir acknowledged the safety issues but in a misplaced attempt to play down fears incorrectly stated that 'É the problems were well known.'

A spokesman for Glaxo Welcome commented that 'This has been so well documented that it is very well known, especially within the HIV community,' This is in stark contrast to the EMEA public statement which clearly states that these additional warnings were the result of new information.

 

VOLUME 1 No6 September 2000

TREATMENT ALERT

ddI once or twice daily?

The US Food and Drug Administration (FDA) recently prompted a letter to US health care providers warning against prescribing ddI (didanosine, Videx™) once daily.

This has led to some confusion over the safety of once daily ddI which is compounded by the fact that two formulations of ddI are now available in Europe - the antacid buffered and the enteric coated. Bristol Myers Squibb, the drugs manufacturers have issued the following letter to clarify the current situation.

As HTB went to press, the issue of pharmacokinetic properties of the new ddI/EC 'enteric coated' formulation and food interactions were addressed in a second letter from the company. The text of each letter in included below.

Dear ...

Bristol-Myers Squibb UK has recently received a number of enquiries about the appropriate dosing schedule for Videx. These enquiries follow the circulation of a letter to healthcare providers by BMS in the United States, at the request of the Food and Drug Administration (FDA). We would like to take this opportunity to keep you fully informed about the circumstances surrounding this letter in order that you may continue to use Videx with confidence.

In the UK, Videx is approved for dosing once daily (OD) or twice daily (BD)1. The once daily indication was approved in June 1999, and is based upon the results of clinical trials which demonstrated that OD and BD dosing of Videx are comparable. The development of different dosing regimens reflects BMS's commitment to continuing to improve Videx formulations.

In the US, Videx has also been approved for OD or BD dosing. Based upon the results of clinical trial AI454-148 (an Open Label registrational study for once daily dosing with 200mg tablets) a clarification has now been issued by BMS in the United States only, the precise wording of which is as follows:

"The preferred dosing frequency of Videx is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of Videx."

This study was not a comparison of OD versus BD, and therefore no conclusions can be drawn about the relative merits of OD versus BD from this study. You will note that the letter retains the option for OD dosing - it does not contraindicate the OD option. It simply states that there is historically more data to support BD than OD dosing, which reflects the dosing interval of the first Product Licence for Videx.

Historical summary of product licences
Year United Kingdom United States
1998 BD   BD      
1999 BD or OD BD or OD
2000 BD or OD BD or OD under certain circumstances

Clinical trial AI454-148 2

Study A 1454-148: study design

Multinational, prospective, open-label, randomised study (n=758)

ddI QD (2 x 200mg) + d4T + NFV (n = 503)

vs

AZT + 3TC + NFV (n - 243)

Thymidine analogues could be switched for intolerance without patients being considered 'failure'

Figure.1: Study Design

Study A 1454-148: study objectives

Primary Objective:

to show equivalent antiretroviral efficacy based upon HIV RNA < 400 at 48 weeks

 

Figure 2: Study Objectives

The following figures (figures 1 and 2) give the background to this study:

The 48-week results of this study, based on an FDA modified statistical analysis which included all randomised patients rather than the protocol specified treated population, have recently been released and are as follows:

Study arm HIV RNA <400 copies/mL (as randomised)
ddI, d4T, nelfinavir 50%
AZT, 3TC, nelfinavir 59%
p value <0.05

Thus, by the FDA-defined criteria for similarity the conclusion of similar efficacy between the regimens could not be drawn. CD4 responses were comparable between the arms.

There are several possibilities that should be considered, and to some extent these reflect clinical practice several years ago when the study was initiated:

Statistical methodology: this difference may in part be due to choices of statistical methodology.

In the original study design, patients were allowed to switch therapies (e.g. specifically AZT to d4T, or vice versa) due to intolerance, and would still be counted as being in their original randomised arm. This is because it was primarily a study looking at ddI rather than the accompanying nucleosides. The assumption in the protocol for this was that there would be few switches, and these would be equally divided between the regimens. In the event however, this did not happen, as shown in figure 3.

Crucially, significantly more patients switched from AZT to d4T than vice versa, because of AZT-related intolerance (8% versus 3%; p=0.007), yet were analysed as if they remained on AZT. The majority of switches from AZT also occurred in the first 24 weeks of the study, whilst those that occurred for d4T intolerance were mainly later events.

If this is taken into account, and a standard intent-to-treat analysis of 'switch equals failure' is applied (see figure 4), then the two regimens do meet the protocol-defined definition of similarity, as shown in figure 5.

FDA requested analysis of the data in an as randomised fashion. This did not take into account the number of patients who chose not to start therapy and were still included in the 48 week analysis (4% did not start therapy in the ddI/d4t arm versus 2% in the AZT/3TC arm).

Different dosing regimens: nelfinavir used in the study was dosed TID. Since nelfinavir needs to be taken separately from Videx, this effectively rendered the regimen one that needed to be taken at four separate occasions each day.

Side effect profiles of components of regimens: the use of nelfinavir in the study was based upon its widespread use at the time the study was designed. Nelfinavir is associated with significant levels of side effects, particularly diarrhoea, and it may be that its use with the buffered tablet formulation of Videx had some effect on premature study withdrawals.

Videx once daily is effective

Since June 1999 Videx has been approved for OD or BD dosing. Since that time several studies have shown that once daily dosing with Videx is effective. These include AI454-143 3, AI454-1464, Virgo 5, SCAN 6, Atlantic 7. Results from the START II study have recently been published and show that d4T/ddI/IDV is at least comparable to AZT/3TC/IDV 8. Thus we believe that we have robust data to fully support the continued once-daily dosing regimen for Videx.

Please note that Bristol-Myers Squibb is preparing a data package for submission to the European Health Authorities for inclusion of this new data into the label for Videx. The results of the studies listed above will also be submitted.

Please do not hesitate to contact us if you would like to discuss any of these matters, or if you would like a copy of the slides shown in this letter.

Yours sincerely,

BEN WILLS, Virology Scientific Adviser

AJAY DUGGAL, Virology Medical Adviser

References:

  1. Videx Summary of Product Characteristics, Dec ember 1999
  2. BMS data on file
  3. Mobley JE et al. AIDS 1999; 13(11): F87-F93
  4. Monno L et al. Antiviral Ther 1999; 4: 195-202
  5. Raffi F et al. 39th ICAAC, September 1999, San Francisco, USA; p519, abstract 1978
  6. Garcia F et al. 6th CROI, February 1999, Chicago, USA; Abs 628
  7. Katlama C et al. 6th CROI, February 1999, Chicago, USA; Abs 18.
  8. Eron JJ et al. AIDS 2000; 14: 1601-1610.

 

 

VOLUME 1 No6 September 2000

BRISTOL-MYERS SQUIBB PHARMACEUTICALS LTD

September 2000

Medical Information Department KH

Re: Videx® EC (ddI, didanosine) - Food Restrictions

Formulation

Videx EC is a different formulation to Videx chewable / dispersible tablets and as such demonstrates a different absorption pattern.

Named Patient Supply

On the 17th April 2000, Bristol-Myers Squibb, commenced the supply of Videx EC on a named patient basis. At that time, data about timing of administration in relation to food was only available for the existing licensed formulation of Videx chewable tablets. In the written guidance provided to healthcare professionals it was recommended that Videx EC capsules were taken "30 minutes before food and 2 hours after food", consistent with the licence for the existing Videx tablet formulation. Under the conditions of the named patient provision of any drug, the drug is not licensed and so, whilst the company provide guidance on the its use, responsibility for administration of the drug lies with the prescribing physician.

Videx EC licence

Further pharmacokinetic data, including food interaction studies, was submitted to the European regulatory authorities in order to obtain a licence for Videx EC in the UK and other EU countries. The licence was reviewed under the mutual recognition procedure. As part of this procedure all European member states review the submission documents simultaneously. During this review process, one member state raised a query about pre-food dosing of Videx EC and requested that Bristol-Myers Squibb conduct further food interaction studies. This data will further establish the recommended dosing of Videx EC capsules before food.

Videx EC Dosing Recommendations

It is recommended that Videx EC be taken 2 hours after food1. Until further studies have been completed and recommendations established, a precise recommendation for the timing of Videx EC administration prior to eating cannot be made. It is therefore suggested that Videx EC be taken 2 hours after food, a convenient time being before bedtime.

References

Data on File. Bristol-Myers Squibb Pharmaceuticals Ltd

comment

Enteric coated ddI is a different formulation to the buffered versions and therefore has its own PK and bioavailibility profile. Discovering that food interactions post- dosing may require an extended fasting period this late in the development process was not expected. The company are now unable to recommend a safe post dose fasting period until the results from this study are analysed.

As these new indictations are very different from those previously provided to patients, clinics should contact patients already enrolled in studies or on the named-patient programme to advise them of the change to pre-dose fasting requirements.As a precautionary measure prior to exact post-dose fasting requirements being known it may be advisable to recommend a similar 2 hour period after dosing before food is taken.

The suggestion to move dosing to last thing at night,rather than first thing in the morning,will provide the greatest change to daily regimens for most patients.

It has also become clear that patients are still not being provided with correct dosing information when prescibed the currently licenced formulations.

It is well established that the 'reduced-mass' 200mg and original 100mg formulations require a fasting period before and after dosing - 'BOTH 30 minutes before food AND 2 hours after food'. While manufacturers are not responsible for information that pharmacies include on the label as patient information, many clinics have been advising '30 minutes before food OR 2 hours after food' on the medicine labels.

Ensuring clear information is always provided to patient labels is particularly important given that doctors and patients have been expecting that the EC formulation would lead to a less restrictive dietary schedule.

 

VOLUME 1 No6 September 2000

TREATMENT STRATEGIES

Structured Treatment Interruptions and Treatment Intensification

Stefano Vella, MD, AIDS Clinical Care, July 2000.

With the realization that eradication of HIV from an infected individual is not an attainable objective at present, antiretroviral treatment has been redirected toward a less ambitious but very strategic goal: the long-term management of a chronic disease.

The best time to initiate antiretroviral therapy and the best initial regimen remain controversial. In order to prevent progressive immune damage, treatment ideally should be initiated as early as possible following infection. The attractiveness of early treatment, however, must be balanced against the drawbacks of prolonging the overall duration of therapy. Indeed, we know that the risk of disease progression is low until substantial CD4-cell count loss has occurred and that immune recovery is impressive even in patients with advanced infection.

Once the decision to start antiretrovirals has been made, however, the ultimate treatment goal should be maximal suppression of HIV replication, because any continuing replication carries the serious short-term risk of spurring the development of drug resistance. Several strategies are now available to achieve viral suppression, especially for persons initiating therapy. Regimens are usually composed of 3 or 4 drugs: 2 NRTIs combined with 1 or 2 PIs or an NNRTI. Regimens consisting of 3 NRTIs are currently being tested.

The superiority of any one of these potent initial regimens over the others has not yet been demonstrated, and sweeping recommendations are not possible. Because future options may be severely compromised by an initial regimen that is insufficiently potent or difficult to comply with, however, individual treatment decisions should be based on the strength of supportive data, tolerability of the regimen, potential for adverse effects, likelihood of important pharmacokinetic interactions, convenience and likelihood of adherence, and potential for subsequent treatment options should the regimen fail. Indeed, treatment failure after a variable amount of time is, unfortunately, quite common.

Reasons are multifactorial and include insufficient potency of the regimen, poor pharmacokinetics, poor adherence, and pre-existing resistance mutations. Given the expected benefits of suppressing viral replication for as long as possible, new therapeutic strategies are needed to maximize the long-term effectiveness of antiretroviral treatments. However, recent studies have suggested that induction maintenance therapy is not as effective as researchers had hoped.

This article will review 2 other strategies under investigation: (1) structured treatment interruption aims to increase the immunologic control over viral replication, while giving patients a break in the long and difficult journey through antiretroviral therapy, and (2) treatment intensification aims to avoid premature failure of an insufficiently potent antiretroviral regimen.

Structured Treatment Interruption

Structured Treatment Interruptions (STIs) - drug holidays initiated with the clinician's guidance - are being studied for use in patients who have experienced virologic failure on multiple regimens and in patients who have achieved virologic suppression on their current regimen.

STI in Patients with Virologic Failure On Multiple Regimens

STI strategy was originally aimed at patients who had experienced virologic failure on multiple regimens and were left without therapeutic options. The theory was that cessation of treatment might result in reversion of resistant virus to wild type, thus allowing for the recycling of antiretroviral drugs. Unfortunately, neither V. Miller (the first scientist to propose and test this approach) nor S. Deeks has been able to confirm the encouraging preliminary results Miller obtained in 1999. STI frequently results in reversion to the wild-type virus in plasma, but the same does not occur in cell-associated virus. In addition, a marked increase in viral fitness occurs during therapy interruption. Finally, STI is associated with heavy decreases in patients' CD4-cell counts, which may be associated with a high incidence of new adverse clinical events. Taken together, these data cast serious doubt on STI in patients with advanced HIV disease.

However, although no controlled clinical data exist, the majority of participants in pilot studies have experienced favourable changes in their HIV drug-resistance during treatment interruption. Resistance assays performed on peripheral blood samples in patients still taking their failing drug regimens showed a number of resistance-associated mutations in HIV reverse transcriptase and protease genes. After approximately 1 to 2 months off therapy, these genetic changes were less detectable as measured by both genotypic and phenotypic assays.

STI in Fully Suppressed Patients

A very different philosophy underlies the use of STI in patients who have achieved complete and persistent viral suppression. There is evidence that specific and effective cellular immune responses to HIV occur in infected subjects. As a result, researchers have explored alternative approaches to HIV therapy aimed at enhancing the host's immune response. Encouraging results have been obtained with interleukin-2 and with HIV-derived immunogen therapies, and studies of other immunologic intervention strategies are ongoing. Effective control of HIV by a specific CD4-cell response in long-term nonprogressors suggests that enhancing the immune response may lead to a stable equilibrium between virus and host.

In this context, STI represents a promising approach to immune boosting. The hope is that short treatment interruptions will augment the length and strength of host immune responses to HIV. However, in the few completed uncontrolled studies of treatment interruptions, the majority of patients experienced a rapid viral-load rebound and a rapid decline in CD4-cell counts. As a result, the potential immunologic effectiveness of STI remains a matter of controversy to be clarified by controlled clinical trials.

The first uncontrolled trial of STI was essentially a "proof of concept," demonstrating that HIV eradication is an unfeasible and unrealistic objective. However, this study also provided some basic data concerning CD4-cell and viral dynamics during therapy interruption and reinstitution. In further reports, Davey and colleagues showed that the viral-load rebound seen during therapy interruption was associated with a re-expansion of latently infected memory CD4 cells.

At approximately the same time, 2 isolated reports in the scientific literature (one of which described the much-discussed "Berlin patient") seemed to suggest that interrupting antiretroviral treatment in patients who had achieved "undetectable" viral loads might result in exposing immune cells to "forgot-ten" viral antigens, thereby activating specific CD4-lymphoproliferative and CD8-cytotoxic responses. In theory, this sort of endogenous vaccination might even be more effective than therapeutic vaccines based on exogenous viral sequences. Several small clinical trials were then conducted in various countries to verify the effects of STI of limited duration (usually no more than 4 weeks) in HIV-positive patients with fully and persistently suppressed viral replication. Despite the many differences in study design, some general conclusions can be drawn from these trials:

  1. STIs, at least in the approaches tested to date, appear to be safe; the HIV during viral rebound shows a conserved drug susceptibility profile, and reinstitution of treatment promptly results in a reduction in viral load and an increase in CD4-cell count.

  2. An increase in HIV-specific CD4-lymphoproliferative activity and some favourable effects on the breadth and magnitude of CTL response has been observed in varying proportions of patients across these studies. However, it remains unclear how long these STI-induced immune responses persist.

  3. A few cases have shown a reduced virologic set point after repeated STIs, although we do not know if this reduction is due to treatment interruption or if it is just a casual event.

Giving Patients a Break

STI may have a third and larger role in antiretroviral therapy, beyond battling resistance in patients with virologic failure or boosting immune responses in patients with virologic success. For as long as there has been antiretroviral therapy for HIV, patients have interrupted it. Treatment interruptions have occurred because of drug toxicity, intercurrent illness, boredom with treatment, chaotic life style, uncertainty over therapeutic advice, and many other reasons. In the early years of antiretroviral therapy, forced treatment interruptions were commonplace when patients experienced toxic reactions - because no new drugs were available. Now that there are more licensed antiretroviral agents, patients usually can change from regimen to regimen without needing to stop treatment, at least initially.

Many patients still wish to stop therapy temporarily (or permanently), for a particular social or medical reason - or for no stated reason whatsoever - and unplanned treatment interruptions are commonplace. While some patients can discuss treatment interruption with their physicians, others find this difficult, and many months may pass before their clinicians discover that treatment has ceased. Short unplanned treatment interruptions occur when pills are left at home, patients become forgetful, or life just becomes too complex.

We know that antiretroviral treatment has long-term toxicity and low tolerability and that it decreases quality of life for asymptomatic patients. Furthermore, clinical practice tells us that (1) at any given time, one third of patients on potent antiretroviral treatment have a viral load of more than 20,000 copies/ml, (2) unplanned treatment interruptions are common, and (3) virologic and immunologic failure and drug resistance occur at significant rates. The question becomes: Can we expect to keep people on antiretroviral therapy indefinitely, or should we try to give patients a break under certain circumstances, setting our sights on the larger goal of increasing their overall exposure to antiretroviral treatment? Interest is rising in using STI (also known in this context as "intermittent" or "pulse" therapy) to give patients just such a break from antiretroviral therapy's associated toxicities and adherence burdens, with the ultimate goal of prolonging the beneficial effects of treatment. In addition, this strategy could have an unprecedented, positive effect on the treatment of HIV in resource-poor settings, from urban America to the developing world.

However, many questions still need to be answered in controlled trials before STI can be adopted in clinical practice:

"The current paradigm of HIV treatment is that it must be continuous throughout the patient's life," according to Mike Youle, the researcher who first proposed testing STI in clinical trials. "The assumption - based on our present knowledge of HIV viral dynamics and antiretroviral therapy - is that cessation of treatment would soon lead to reversion to pretreatment clinical status and be detrimental to the patient. However, the first studies of interrupting HIV treatment appear to challenge this assumption and offer evidence that the virus is more forgiving than we had previously believed."

STI may have distinct attractions for patients and healthcare providers, offering the potential for reduced toxicity, improved tolerance, increased adherence, and lower cost. The ability to reuse drugs that had ceased to be effective and to reduce the overall exposure to antiretroviral agents is invaluable, especially given the limited number of available drugs. We must now eagerly await the results of controlled clinical trials. In the meantime, however, the use of STI outside of the clinical research setting must be discouraged.

Treatment Intensification

Despite the apparently wide array of available antiretroviral agents and the high number of theoretical combinations, cross-resistance among drugs of the same class limits therapeutic options. Thus, all efforts should be directed toward prolonging the effect of the initial antiretroviral treatment. Indeed, many controlled studies have proven that the nadir of a patient's initial response correlates well with the durability of his or her response, and that achieving an early sustained response (by week 4 or 8 of therapy) is predictive of subsequent virologic suppression. Viral-load levels should therefore decrease by a minimum of 1.5 to 2.0 log over the first 4 weeks of therapy, and failure to achieve the target level of less than 50 copies/ml by 16 to 24 weeks should raise concern about patient adherence, drug absorption, or drug-resistant virus - although in patients with higher viral loads (e.g., more than 100,000 copies/ml) maximal viral suppression may take longer.

Intensification strategy represents an experimental approach to antiretroviral therapy designed to prolong the life of the initial regimen. Theoretically, it has applications in 2 different situations: (1) failure to establish initial control of virus replication and (2) "early" treatment failure after initial complete virologic response. (See Figures 1 and 2.) In persons with a low but detectable viral load following 12 to 16 weeks of potent antiretroviral therapy or in persons with early viral-load rebound after full suppression, the addition of a new drug could be an alternative to a complete regimen change, after other causes of treatment failure (notably incomplete adherence or drug resistance) are ruled out. One of the main goals of treatment intensification is the preservation of therapeutic options. Thus, drugs that can be used for intensification include agents from classes already represented in the regimen (preserving other classes in the event that intensification proves unsuccessful) or agents with high genetic barriers to resistance.

There are serious potential drawbacks to treatment intensification. Patient adherence is notoriously difficult to assess. Genotypic and phenotypic resistance testing, although promising, are still new features in clinical practice, and drug resistance can be difficult to rule out. In fact, given the thin line between intensification and incremental therapy, intensification may promote further drug resistance if it is already developing. Moreover, intensification may aggravate adherence problems and may intensify the level of adverse pharmacokinetic interactions. Further controlled studies of treatment intensification are certainly needed before this strategy can be used in standard clinical practice.

Conclusion

Over the past few years, HIV/AIDS - at least in developed nations - has been transformed into a chronic, treatable illness. Patients and clinicians are now in need of new therapeutic strategies to maximize the beneficial effects of the available antiretroviral drugs. STI and, to a lesser extent, treatment intensification represent promising new approaches to HIV care and merit intensive study.

References

  1. Altfield M et al. Increase in breadth and frequency of CTL responses after structured therapy interruptions in individuals treated with HAART during acute HIV-1 infection. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  2. Carcelain G, et al. Intermittent interruptions of antiretroviral therapy in chronically HIV-infected patients do not induce immune control of HIV. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  3. Carpenter C J et al. Antiretroviral therapy in adults. JAMA 2000; 283:381-390.
  4. Carr A et al. Diagnosis, prediction and natural course of HIV-1 protease inhibitor associated lipodystrophy, hyperlipidaemia and diabetes mellitus. Lancet 1999 ; 353:2093-2099.
  5. Davey R et al. The NoHRT trial: a prospective study of cessation of HAART in HIV-infected patients after prolonged viral suppression. 39th ICAAC, San Francisco 1999
  6. Deeks SG et al. Virologic and immunologic evaluation of structured treatment interruptions (STI) in patients experiencing long-term virologic failure. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  7. Devereux H et al. Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS 1999 ; 13:F123-F127.
  8. Finzi D et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1. Nat Med 1999 ; 5:512-517.
  9. Garcia F et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 1999 ; 13:F79-F86.
  10. Garcia F et al. Structured cyclic antiretroviral therapy interruption (STI) in chronic infection may induce immune responses against HIV-1 antigens associated with spontaneous drop in viral load. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  11. Hatano H et al. Plasma viral loads approximate pre-HAART levels after discontinuation of HAART. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  12. Jin X et al. Discontinuation of HAART after a course of therapeutic vaccination with ALVAC1452 and rgp160 may be associated with delayed viral rebound kinetics. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  13. Lori F et al. Control of viremia after treatment interruption. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  14. Neumann A et al. HIV-rebound during interruption of highly antiretroviral therapy has no deleterious effect on reinitiated treatment. AIDS 1999 ; 13:677-683.
  15. Pallela F et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998 ; 338:853-860.
  16. Papasavvas E et al. Boosting of HIV-1-specific cellular immune responses in chronically infected persons after treatment interruption. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  17. Ruiz L et al. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. 7th European Conference on Clinical Aspects and Treatment of HIV Infection, Lisbon 1999
  18. Ruiz L et al. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  19. Sherer R et al. No detectable HIV RNA in thirteen individuals months after stopping antiretroviral therapy. 7th Conference on Retroviruses & Opportunistic Infections, San Francisco 2000
  20. Youle M et al. Surrogate marker responses to multidrug combinations comprising hydroxyurea, efavirenz, double protease inhibitors and nucleoside analogues in protease inhibitor failures. 6th Conference on Retroviruses & Opportunistic Infections, Chicago 1999
  21. Youle M. Is interrupting HIV Therapy always harmful? J Antimicrob Chemotherapy 2000 ; 415:1-2.

Source: http://www.accnewsletter.org/

comment

The SSIT study, presented at Geneva, but not listed was, overall, negative although the presentation involved clutching at 'encouraging' individual patient data. One patient developed documented 3TC NFV resistance, another 'failed' to reinduce full suppression over 8 weeks. CD4 cell counts stayed flat, instead of the rise we might expect over one year appropriate therapy and mean VL rebound did not change.

Interruption schedules and timing remains poorly defined and may have a crucial role to play in any likely successes with this approach. Further research is required to more clearly define the role of controlled bursts of viraemia and possible dangers.

 

VOLUME 1 No6 September 2000

 

Importance of protease inhibitor plasma levels in patients treated with genotypic-guided therapy

Polly Clayden, HIV i-Base

A report published in the July issue of AIDS showed greater decline in viral load in subjects with optimal PI plasma concentrations (OC) compared to those with sub-optimal concentrations (SOC).

81 trial participants on failing therapy (defined as viral load over 10,000 copies/ml and at least 6 months of treatment with nucleosides and 3 months with protease inhibitors) in this PK sub-study were randomised to receive either standard (control group) or genotypic-guided therapy. Serial plasma levels were taken throughout the twelve-month study period. SOC was defined as at least two plasma levels below 2xIC95. Subjects fell into four categories: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype) and G4 (OC/genotype).

It was revealed that 67.9% of patients had OC and 32.1% SOC and this correlated significantly with reductions in HIV-1 RNA which fell by 1.4 log and O.36 log respectively by week 48.

There were also significant differences in the group treated with genotypic-guided therapy. At month 6 the mean changes in HIV-RNA from baseline were: G1 - 0.23+/0.29 log 10 copies/ml; G2 - 0.97+/-2.8; G3 - 0.68+/-0.37; G4 - 1.38+/0.20. In multivariate analyses optimal PI concentration, use of genotyping and presence of PI resistance were all implicated in viral load response.

The investigators concluded that other causes besides PI resistance contributed to therapeutic failure, and that 'Sub-optimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimising antiretroviral therapy.'

Reference:

Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guide therapy: pharmacological data from the Viradapt study. Durant et al AIDS 2000 July 7; 14 (10): 1333-9

comment

Ritonavir boosted PI is now the rapidly developing standard of care to ensure adequate PK and dosing schedules/requirements that can be lived with. However, regular therapeutic drug monitoring should ensure those on single PI's are maintaining adequate blood levels.

 

VOLUME 1 No6 September 2000

PATHOGENESIS

Scrub Typhus: Infection Reduces Viral Load in Some Patients

John S. James, AIDS Treatment News

An accidental discovery in Thailand led researchers at the U.S. Armed Forces Research Institute of Medical Sciences in Bangkok and several other U.S. and Thai medical institutions to conduct additional research which found that the disease scrub typhus can produce unknown HIV suppressive factors, possibly certain antibodies, that can reduce HIV replication. This is the first infection known which can reduce HIV viral load (most infections increase HIV viral load temporarily). A five-page article on the finding was published recently in The Lancet.

Scrub typhus, caused by bacteria, is common in parts of Asia; it is easily treated with antibiotics, but if untreated, varies in severity from mild to fatal. In this study patients received antibiotics for scrub typhus, but no antiretrovirals. The degree of HIV suppression varied greatly; the average viral load of the patients studied appears to have increased, although not as much as with other illnesses.

However, two of the 10 patients with scrub typhus who were tested in this study had viral loads become temporarily undetectable, and they were also negative for HIV DNA (using a PCR test) - even though all had advanced AIDS, with CD4 counts ranging from 7 to 161 when first admitted to the hospital. And two other patients in that group of ten also had substantial drops in their viral load. [No baseline viral load was available, as patients were already ill with scrub typhus when they came to the hospital, and their viral load may have already been affected; therefore their viral load during the illness was compared with the value at day 28, after their bacterial infection had been successfully treated and the viral load had presumably returned toward its usual set point.]

The great variation in anti-HIV effect suggests that perhaps only some scrub typhus bacteria produce the right antibodies or other factors to inhibit HIV.

A possible mechanism of action for the HIV suppression is the prevention of syncytia, clusters of cells which abnormally merge, become infected, and die. All 10 of the scrub typhus patients has NSI (non-syncytia-inducing) virus, while five of seven comparison patients who did not have scrub typhus has SI (syncytia-inducing) virus.

In another test, serum from an HIV-negative scrub-typhus patient strongly inhibited HIV in a laboratory test. Depletion of antibodies from the serum significantly reduced this effect.

Interestingly, scrub typhus is not more severe in HIV- positive than in HIV-negative persons - and one study found a lower, not higher, rate of positive scrub typhus blood culture in persons who are HIV positive.

An August 8 report by the wire service Agence France-Presse noted that in Thailand, 300,000 people have already died of AIDS, and fewer than 10% of HIV patients can afford the antiviral combinations used in richer countries. Researcher Dr. George Watt, quoted in the report, said that antibodies to scrub typhus could potentially be a very inexpensive treatment. "Every day at the hospital in Chiang Rai we have to tell dying HIV patients, 'Yes, there is treatment for HIV, but it's too expensive for you." So the motivation is there for the scrub typhus work."

Reference:

Watt G, Kantipong P, de Souza M, and others. HIV-1 suppression during acute scrub-typhus infection. The Lancet. August 5, 2000; volume 356, pages 475-479.

Source: AIDS Treatment News: Copyright 2000 by John S. James. Subscription and Editorial Office: P.O. Box 411256, San Francisco, CA 94141. 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number.

comment

This interesting observation clearly needs to be further defined. This may be the first infection to not upregulate HIV transiently. Therapeutic spin-offs may be an intriguing possibility.

 

VOLUME 1 No6 September 2000

Duration of incubation affects subsequent rate of HIV disease progression

Paul Blanchard, HIV i-Base

Dr Phillipe Vanhems and associates at the Universite Claude Bernard in Lyon investigated the relationship between incubation time before the onset of acute HIV-infection and time to an AIDS defining event. The prospective study of 70 patients identified the date of HIV-infection, onset of symptomatic acute infection and time to an AIDS defining event.

Median incubation time (from 'inoculation' to acute infection) was 21.5 days with a range of 5 to 70 days. The duration and severity of acute infection was found to be unrelated to the duration of incubation. There was, however, a significant association between the duration of incubation and time to first AIDS defining event. Median time to AIDS was 3.82 years for patients whose incubation time was less than the median and 5.05 years for patients whose incubation time was above the median.

The mechanism by which incubation time affects rate of disease progression is unknown but may involve variations in both host immunity and viral replicative capacities.

Reference:

Vanhems P; Hirschel B; Phillips AN et al. Incubation time of acute human immunodeficiency virus (HIV) infection and duration of acute HIV infection are independent prognostic factors of progression to AIDS. J Infect Dis 2000 Jul;182(1):334-7.

 

VOLUME 1 No6 September 2000

IMMUNOLOGY

Population of HIV-targeted CD8 cells fluctuates with viral load during chronic infection

The population of HIV-specific CD8 T cells declines with extended use of effective antiretroviral therapies in infected patients. However, CD8 T cells are remobilised during viral rebound as a result of treatment interruption or failure, according to a report in the August 1st issue of the Journal of Immunology.

"Such dynamics of virus-specific CD8 T cells should be taken into account when elaborating future strategies of scheduled antiretroviral treatment interruptions aiming at restoring specific defenses against HIV," Dr Brigitte Autran, of the Centre National de la Recherche Scientifique, Paris, France, and members of the RESTIM and COMET study groups, conclude.

The researchers evaluated the association between viral load and HIV-specific CD8 cell populations in 15 chronically infected patients receiving highly active antiretroviral therapy. They were able to monitor the existence of 16 different cytotoxic T-cell epitopes in 14 of the patients.

During the first month of treatment, viral load decreased rapidly. At the same time, the population of HIV-specific CD8 cells in the peripheral blood tripled, while 8 new HIV-specific epitopes, as well as previously undetectable cytomegalovirus-specific epitopes, appeared.

With extended suppression of viral load, the population of HIV-specific CD8 cells in the patients declined, Dr Autran's group found. But these cells remain capable of remobilisation, as "rebounds of HIV replication are paralleled by peaks in memory CD8 T lymphocytes that quickly restore the pre-existing host-virus quasi-equilibrium," they write.

Specifically, the authors observed 4 patterns of epitope-specific CD8 cell dynamics during viral rebound: "peaks or disappearance of pre-existing specificities, emergence of new specificities or lack of changes."

Dr Autran's group concludes that these dynamics may have an impact on therapeutic interruption strategies aimed at increasing the host response to HIV.

Ref: J Immunol. 2000;165:1692-1704.

Source: Reuters Health

 

VOLUME 1 No6 September 2000

Murabutide inhibits HIV replication in macrophages and dendritic cells

The synthetic immunomodulator Murabutide inhibits HIV replication in macrophages and dendritic cells through multiple mechanisms, according to researchers in France, who suggest that the potential of Murabutide as an adjuvant to antiretroviral therapy should be explored.

Macrophages and dendritic cells are CD4-expressing antigen-presenting cells that are important in establishing and maintaining HIV infection, Dr George M. Bahr of the Institut Pasteur de Lille and colleagues explain. They therefore examined the ability of Murabutide to suppress HIV replication in monocyte-derived versions of these cell types.

As they report in the September issue of the Journal of Virology, Murabutide was highly efficient at suppressing viral replication in both cell types without affecting viral entry, reverse transcriptase activity, or early cytoplasmic proviral DNA formation.

The authors also observed that Murabutide inhibited replication by reducing proviral DNA integration and viral messenger RNA transcription, which did not occur by inhibition of cellular DNA synthesis or activation of p38 mitogen-activated protein kinase.

In addition, Dr Bahr and colleagues found that Murabutide reduced cellular expression of CD4 and CCR5 and led to secretion of high levels of beta-chemokines. However, the beta-chemokines were not necessary for the drug to inhibit HIV-1 replication.

"Our findings demonstrate a potent HIV-suppressive activity of a safe synthetic immunomodulator and a profile of antigen-presenting cell activation that is associated with protective responses against infection," they conclude.

The authors note that Murabutide also inhibits HIV replication in T cells and in the humanized severe combined immunodeficient mouse model. "Confirmation of these results and the good clinical tolerance of Murabutide by HIV-infected patients may rapidly contribute to the serious evaluation of a new immunotherapeutic approach, as an adjunct to antiretroviral agents, in the management of HIV disease," the researchers write.

Ref:J Virol 2000;74:7794-7802.

Source: Reuters Health

 

VOLUME 1 No6 September 2000

PAEDIATRICS

Adverse effects of perinatal zidovudine exposure on HIV-infected infants

Polly Clayden, HIV i-Base

A report published in the July issue of the Journal of Infectious Diseases compared the clinical progression of HIV disease, among infected infants either exposed or unexposed to zidovudine pre or perinatally.

Dr Louise Kuhn's group followed 325 HIV-infected children born during 1986 to 1997 in a multicentre observational cohort study, until AIDS diagnosis or death. Among the children who did not receive antiretroviral therapy before AIDS diagnosis, 44% of the zidovudine-exposed group (vs. 24% of the unexposed) progressed to AIDS or died before the age of 12 months. An alarming 1.8 fold increased risk.

Unsurprisingly none of the infected children treated with multi drug therapy in their first year progressed to AIDS or died during this period, regardless of their prenatal or perinatal zidovudine exposure.

Reference:

Kuhn L et al. Disease progression and early viral dynamics in HIV-infected children exposed to zidovudine during prenatal and perinatal periods. J Infect Dis. 2000 Jul;182(1):104-11.

comment

It is speculated that the mothers using ZDV prophylaxis and subsequently transmitted may have had and therefore transmitted more aggressive disease - but no maternal viral load data was available. It is reassuring that HAART for the children was subsequently effective.

 

VOLUME 1 No6 September 2000

Early cognitive and motor developmental delays in HIV-infected infants

Polly Clayden, HIV i-Base

A report published in the August edition of Pediatrics describes the results of an examination of neurodevelopment in infants born to HIV-infected mothers.

Dr Cynthia Chase's group assessed neurodevelopment of 595 infants in a multicentre, prospective, natural history cohort study, for the Women and Infants Transmission Study (WITS). Analyses were performed on 114 infected and 481 uninfected infants. In Bayley Scales of Infant Development Mental Developmental Index (MDI), the incidence of MDI<69 was 16.5% by 12 months and 35.6% by 24 months in infected infants, compared to 3.2% by 12 months and 8.2% by 24 months in the uninfected group. A decline in score on the Psychomotor Developmental Index (PDI) of at least 2 standard deviations was noted in the HIV-infected group. The investigators reported that a child with HIV-infection is more than twice as likely to experience such a decline compared to an uninfected child. Differences between infected and uninfected infants were apparent as early as 4 months of age.

In their conclusion the investigators stated that a challenge is the 'prompt and reliable identification of infants and children at high risk for central nervous system disease progression, before the onset of encephalopathy, to initiate early, aggressive initiation of preventing devastating effects of HIV on the developing brain.'

Reference:

Chase C et al Early cognitive and motor development among infants born to women infected with HIV. Pediatrics. 2000 Aug;106(2):E25.

 

VOLUME 1 No6 September 2000

Topical cidofovir clears severe molluscum contagiosum in children with AIDS

Topical 3% cidofovir was successful in clearing disseminated molluscum contagiosum refractory to other treatment in 2 children with AIDS, according to Dr Jorge R. Toro and colleagues from the National Cancer Institute in Bethesda, Md.

Previous treatments had included liquid nitrogen, cantharidin, and tretinoin gel. Both patients had been on highly active antiretroviral therapy (HAART) for a median of 24 months.

The facial lesions were so disfiguring that the patients, an 8-year-old boy and a 4-year-old boy, experienced severe social isolation. The CD4 T-cell counts were 329 and 168 cells/µL, with viral loads of log 5.86 and log 5.63 HIV RNA copies/mL, respectively.

In an interview with Reuters Health, Dr Toro pointed out that "If you're treating patients with HAART and the viral load doesn't go down, then you are talking about a very resistant kind of situation."

Cidofovir was mixed with Dermovan, a combination vehicle containing propylene glycol, and applied to lesions once a day, 5 days a week, for 8 weeks. Nonfacial and nonmucosal lesions were also occluded with adhesive tape for at least 12 hours at each application, Dr Toro told Reuters Health.

Five to 15 days after beginning the cidofovir treatment, both boys exhibited redness and painful erosions at the sites of the previous lesions, although surrounding skin was unaffected. "After 2 months of treatment, all the lesions that were treated showed complete clinical resolution," the investigators write.

"The success of treatment is very dependent on the vehicle," Dr Toro said. He explained that a commercially available preparation of 1% cidofovir uses a completely different vehicle. "For patients using that specific type, it didn't work," he said, adding that "It has to be compounded in this particular vehicle and it has to be fresh and it has to be kept refrigerated.

"We saw 1 of the boys 2 weeks ago, and there's been no recurrence of any lesions after more than 2 years," Dr Toro said.

Ref:

Arch Dermatol. 2000;136:983-985.

Source: Reuters Health

 

VOLUME 1 No6 September 2000

NEWER ANTIRETROVIRALS

Flavopiridol inhibits cellular processes essential to replication of HIV

Paul Blanchard, HIV i-Base

Research published in the Journal of Biological Chemistry suggests that flavopiridol, a drug already undergoing clinical trials as a cancer treatment, may also have potential as an anti-HIV therapy. A team at the University of California, San Francisco, discovered that very low concentrations of flavopiridol blocked HIV-1 replication in cell culture experiments.

Flavopiridol is a novel semisynthetic flavone which was first isolated from an Indian plant source in the Hoechst Research Centre, Mumbai, India. Hoechst has subsequently merged with Rhone-Poulenc to create Aventis Pharma a multinational company with a strong presence in Germany (headquarters in Frankfurt) and France. Aventis are currently carrying out phase II trials for flavopiridol in cancer and are hoping for licensing some time in 2003.

Flavopiridol does not act directly on HIV but on the HIV-infected cell. It inhibits the process of cellular transcription by interfering with the action of the protein kinase P-TEFb. This inhibition prevents the genetic material of HIV, incorporated into the nucleus of the cell, from making copies of itself as the basis of new virions. Although flavopiridol inhibits cellular transcription in most cells HIV transcription appears to be particularly sensitive allowing selective inhibition. Inhibitory concentrations determined to be effective against HIV would also allow dosing of flavopiridol lower than that currently being used in cancer chemotherapy where diarrhoea and proinflammatory syndrome affect tolerability. Flavopiridol is the most potent inhibitor of P-TEFb discovered to date in addition to being the only compound so advanced in clinical trials.

Cellular processes are an attractive target for anti-HIV drugs such as flavopiridol. Viral resistance to drugs which target HIV directly can occur rapidly due to selection of viral strains with genotypic resistance. Cellular processes are not, however, susceptible to mutation and resistance. It is therefore unlikely that viral resistance to flavopiridol would occur. Other drugs targeting cellular processes currently being used for HIV therapy include hydroxyurea and mycophenalate mofetil.

Lead investigator Prof. David Price commented that 'since P-TEFb is a key factor in HIV-1 infection and flavopiridol blocks HIV-1 propagation in culture, we believe that this substance should be tested as a potential anti-AIDS drug'.

Reference:

Chao S, Koh F, Marion JE et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem Online. July 21, 2000, 2000.

Full paper available at:

www.jbc.org/cgi/reprint/C000446200v1.pdf

comment

Rapid testing in HIV-infected subjects should be investigated and support from the activist community offered to a company with little experience in HIV therapeutics. There may be potential for salvage in those with multidrug resistant HIV with this compound.

 

VOLUME 1 No6 September 2000

Abbott expands early-access program for ABT-378/r (Kaletra™)

Abbott Laboratories have announced that more HIV-positive patients will now have access to its investigational protease inhibitor Kaletra (lopinavir/ritonavir) via the company's Early Access Program.

The company, based in Abbott Park, Ill, relaxed the criteria that HIV-positive patients must meet to receive Kaletra, formerly ABT-378/r. The drug will now be available to any HIV-positive patient who needs it to "construct a viable regimen, without CD4 cell count or viral load restrictions," Abbott said in a news release.

Because of a limited supply of the drug, which is currently in phase III trials, Abbott's Early Access Program was previously open only to patients with HIV who met select entry criteria.

Developed in cooperation with key regulatory agencies and HIV advocacy groups, Abbott's Kaletra Early Access Program operates in 21 countries worldwide and has enrolled 6100 patients with advanced HIV.

comment

Some UK physicians are still unaware that ABT-378 is available on named patient and open access studies. Interested physicians should contact Abbott in the UK on: 01628 644 370.

 

VOLUME 1 No6 September 2000

Roche and Trimeris Announce Intention to Manufacture Commercial Supplies of Anti-HIV Fusion Inhibitor T-20

Hoffmann-La Roche and Trimeris, Inc. have announced that the Roche manufacturing facility in Boulder, Colorado has been selected to manufacture commercial supplies of the investigational anti-HIV compound, T-20, the first of a new class of drugs called fusion inhibitors which is being co-developed by Roche and Trimeris.

Fusion inhibitors block fusion of HIV with host cells before the virus enters the cell and begins its replication process. Development of this new anti-HIV drug class is considered important, especially for use by HIV patients who have multi-drug- resistant HIV strains and are failing on current HIV therapy.

There has been a concern that development of T-20 could be significantly delayed, due to the difficulties encountered in manufacturing commercial quantities of the compound. In particular, the HIV patient advocacy community has been closely monitoring the drug's development, in the hope that the compound could be made available soon through an "expanded access" program. These programs traditionally have made promising experimental drugs available prior to regulatory approval to patients in need of additional treatment options.

"We have committed substantial financial and technical resources, so that we can start scaling up to produce this peptide in metric tons rather than kilograms," said David Reddy, PhD, Virology Franchise leader, Roche. "This is because we recognize the therapeutic potential that T-20 may have for the growing number of patients in need of new options to control their HIV infection.

The production of peptides in such quantities represents a major challenge that we are pleased to undertake. We encountered similar challenges when the protease inhibitors were first introduced. Trimeris has already transferred the production process to Roche Colorado, where dedicated manufacturing capability has been established and manufacturing for clinical supply has been successfully initiated.

Source: Business Wire - August 24, 2000.

comment

We look forward to the rapid roll out of the promised access programmes. This commitment to scaling up manufacturing capability will initially be required in order to first meet the supply issues for the Phase 3 planned to start enrolment in Europe and the US this year. An expanded access programme for T-20 is still not expected before the end of next year.

 

VOLUME 1 No6 September 2000

PRO 542 shows efficacy in trial

Polly Clayden, HIV i-Base

A report in the July issue of the Journal of Infected Diseases of a phase 1 study of PRO 542 - a recombinant antibody-like fusion protein that binds to and neutralises HIV-1 isolates, showed significant viral load reduction, good tolerability and no dose limiting toxicities, in HIV-infected adults.

Subjects were treated with a single intravenous infusion of PRO 542 at doses of 0.2-10 mg/kg. The drug was well tolerated, and the AUC and peak serum concentrations increased linearly with the dose, as did reduction in HIV-1 RNA. No patient developed antibodies to PRO 542.

Sustained antiviral effect may be achieved with dosing of PRO 542. This novel agent deserves further investigation.

Reference:

Single dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults. Jacobson et al. J of Infect Dis 2000 Jul; 182(1):326-9

 

VOLUME 1 No6 September 2000

OPPORTUNISTIC ILLNESSES

Immunorestitution disease

Polly Clayden, HIV i-Base

Immunorestitution disease (IRD) is the paradoxical clinical deterioration of a pre-existing condition that can sometimes accompany the recovery of the immune system.

A report in the June issue of Clinical Infectious Diseases reviews the sequence of events as occurred previously published reports of IRD in HIV-infected patients after the initiation of HAART. The investigators found that for IRD due to mycobacteriosis (n=27) and cryptococcosis (n=4) the mean interval between the initiation of HAART and the onset of IRD was 11 days; and for viral infections due to cytomegalovirus (n=14), hepatitis B (n=1) and hepatitis C (n=2) the median interval was 42 days.

They concluded that 'As an emerging clinical entity, IRD merits further study to optimise treatment of immunosupressed patients.'

Reference:

Immunorestitution disease involving the innate and adaptive response. Cheng et al. Clin Infect Dis 2000 June; 30(6):882-92

 

VOLUME 1 No6 September 2000

Prevalence of Psoriatic Arthritis Increasing Among HIV-Positive Black Zambians

Increasing numbers of black patients in Zambia are presenting with psoriatic arthritis in association with HIV infection, according to researchers. Psoriatic arthritis has hitherto been rare among the indigenous black peoples of sub-Subharan Africa, they note.

Over a period of 40 months, Dr. Panganani Njobvu, of Stobhill Hospital, Glasgow, Scotland, and a colleague diagnosed psoriatic arthritis in 28 of 702 patients attending an arthritis clinic. Twenty-seven of these 28 patients were HIV-positive, they report.

In 20 patients, "arthritis and psoriasis developed simultaneously," the authors state in their article, published in the July issue of the Journal of Rheumatology. Arthritis preceded psoriasis in four patients, and psoriasis preceded arthritis in the other three patients.

The authors report that most patients had extensive guttate-plaque psoriasis that did not remit with the onset of AIDS. The arthritis usually had an acute onset, "starting in the knees and/or ankle joint in 90% of patients during their first episode." Amelioration of arthritis, although not psoriasis, typically occurred with onset of AIDS.

"This is the largest series yet recorded worldwide in association with HIV infection and this in a setting where psoriatic arthritis was extremely rare," the authors comment.

Given the growing prevalence of psoriatic arthritis among HIV-positive black Zambians, the authors call for increased recognition of this condition "as an HIV-related disorder."

Reference:

J Rheumatol 2000;27:1699-1702.

 

VOLUME 1 No6 September 2000

OTHER NEWS

HAART: Enough to make your hair curl?

Long-term treatment with highly active antiretroviral treatment (HAART), which has been associated with the development of lipodystrophy, may also result in curly hair, according to investigators in Belgium.

Changes from straight to curly hair have also been seen during puberty as a consequence of etretinate and isoretinoid treatment and as a paraneoplastic symptom. Other hair changes during HIV-1 infection, such as straighter and softer hair, have been previously reported, the authors explain.

In the August issue of the Archives of Dermatology, Dr Robert Colebunders, of the Institute of Tropical Medicine in Antwerp and colleagues recount the experience of a 48-year-old heterosexual truck driver first diagnosed with HIV-1 infection in 1991.

After 2 years of HAART, beginning in 1996, the patient noted that his hair had changed from straight to curly. He also developed peripheral lipoatrophy, the authors report.

Seven months after noticing his hair change, the patient was diagnosed with an invasive, moderately differentiated spinocellular epithelioma in the anus. After successful tumour resection and radiotherapy, the patient continued to have c