remAIDES # 31
what's new?

Sustiva, a new anti HIV drug has attracted a lot of attention due to its efficacy (similar to that of protease inhibitors over a one year period), and its ease of administration (once a day). It is nevertheless important to know its side-effects to be able to manage them.

Sustiva’s strong points
Over a one year period, the efficacy of a triple therapy including Sustiva is similar that of a triple therapy including a protease inhibitor. Sustiva can also be associated with protease inhibitors. Sustiva is to be taken once a day (3 capsules) during meals or fasting.
Sustiva might not lead to side-effects which sometimes occur during treatments with protease inhibitors (increase in blood fat levels, change in body aspect due to changes in body fat location). 
Sustiva is widely available in France for persons who have not yet taken protease inhibitors or for whom protease inhibitors have failed or have not been well tolerated. To obtain the drug, your doctor needs to contact Du Pont-Pharma (in France : 0800 87 93 19).

Treatment initiation
In half of the patients, Sustiva leads to vertigo, a feeling of drunkenness or sleep disturbances (insomnia, strange dreams or nightmares). These side-effects appear in the first days of treatment, sometimes as early as on the first day. They usually disappear in 4 to 6 weeks. However in some persons, intense and bothersome disturbances may occur, with a sensation of disorientation or hallucinations. 
In addition, Sustiva may sometimes cause skin rashes (red spots or rashes), or an increase on blood liver enzymes called transaminases.

Medium-term side-effects
With Sustiva, some persons experience psychological disturbances : it may be prudent to inform, ahead of time, close relatives to avoid misunderstandings if mood changes occur. Psychological disturbances such as anxiety attacks or nervous breakdown may appear after several days or weeks of a well-tolerated treatment. In other cases, side effects occurring early on (insomnia, vertigo) may persist and lead to prolonged problems. 
These problems were initially under estimated by Du Pont-Pharma and by most doctors. However, under the pressure of US and French AIDS groups, studies are under way to understand their cause.

Do not decrease dosage
Sustiva doses should not be decreased to try to alleviate side effects, including at treatment initiation. This could lead to the appearance of viruses resistant to this drug and to all drugs of the same family.

What can be done ?
To decrease morning vertigo, it is now recommended to take Sustiva not at dinner time any more, but before going to bed. Also, high fat-containing dinners should be avoided as they increase Sustiva blood levels . Some persons find it better to take one capsule in the morning and two in the evening. This, however, is not recommended during the first 2 weeks of treatment ; after this period of time, efficacy is theoretically the same when the 3 capsules are all taken at the same time.

What to do against loss of sleep or anxiety ?
Sustiva might increase blood levels of some drugs (sleeping pills, drugs against anxiety) and cause longer sleeping times or sleepiness ; this is currently being studied. However, several persons took Sustiva and sleeping pills or drugs against anxiety without any problem ; this should not be done without medical advice. It is advisable to start with half-doses of sleeping pills. Lastly, the most potent drugs of this family (Halcion, Hypnovel) are contra-indicated.

If you just cannot take it
A minority of persons suffer from intense and sustained side-effects with Sustiva. In this situation, a treatment change should be considered with you doctor. Sustiva side-effects usually disappear two to ten days after treatment stop.

As a conclusion
During the June 98 AIDS conference in Geneva, Sustiva was touted as the wonder drug, effective, easy to take and with very few side-effects. Reality is, of course, a little more complicated.

Sustiva and protease inhibitors
With Crixivan (indinavir) : take 1000 mg Crixivan doses instead of 800 mg. Sustiva doses do not need to be changed. 
With Norvir (ritonavir) : no need to change either drug’s dosage. However, their blood levels increase, and this may cause more side-effects. 
Associating Sustiva and Invirase or Fortovase is not advisable, since saquinavir blood levels sharply decrease. For the same reason, the Sustiva and Agenerase (amprenavir) association is clearly not advisable. 
No data are available with Norvir + Invirase. 
Finally, no interaction was shown between Sustiva and nucleosidic drugs (Retrovir, Videx, Hivid, Zerit, Epivir, Ziagen, Combivir).
 

Thierry PRESTEL
Emmanuel TRNADO
 

Sustiva, Viramune and Rescriptor

All three drugs belong to the same family, that of non-nucleosidic drugs. Here are some data which can help choosing among them :

• Sustiva (efavirenz) could be more effective than Viramune (nevirapine) or Rescriptor (delavirdine) in persons with a high pre-treatment viral load;
• Sustiva is sometimes active against viruses which are resistant to Viramune or Rescriptor (reverse case seems rarer);
• Currently, only Viramune has a presentation adapted to small children (powder to make a drinkable solution) ;

These 3 drugs can lead to skin rashes (red spots or rashes), usually during the second treatment week. If a rash appears, quickly consult your doctor to see if this serious (if so, treatment needs to be stopped immediately to avoid a severe allergic reaction), or not serious (treatment can be continued). Skin rashes are frequent with these three drugs (affecting nearly 30% of patients), but rarely serious (less than 1%of cases).

To decrease the chances of skin rashes appearing, it may be helpful to prescribe an anti-allergic drug during the first weeks of treatment. Furthermore, it is advisable to start treatment with half-doses of Viramune (one tablet a day). Conversely, full doses of Rescriptor or Sustiva should always be taken (a lower dose does not reduce the incidence of rashes, but may lead to the appearance of resistant viruses).

In persons with chronic hepatitis taking any of these 3 drugs, it is advisable to assay transaminases (liver enzymes in blood) every week at the beginning of treatment. Major increases seem more frequent with Viramune than with Sustiva or Rescriptor.

With the exception of the side-effects described above, Viramune and Rescriptor seem well tolerated. Unlike Sustiva, they do not cause nervous system disturbances.

These 3 drugs can change several other drugs’ blood levels : it is important to tell your doctor about all the drugs you take to avoid under dosage (and lack of efficacy), or overdosage (and toxicity). When Viramune, Sustiva or Rescriptor are associated with protease inhibitors, dose adjustments may be necessary. To better adjust treatment, anti-HIV drugs can be assayed in blood.

Sustiva is to be taken once a day (three capsules) ; Viramune, twice a day (two times one tablet) ; Rescriptor, three times a day (4 tablets each time ; they can be dissolved in water). These 3 drugs can be taken either during meals or on an empty stomach.

The Chicago congress

go to
https://www.healthcg.com

The yearly US congress on HIV infection took place in Chicago from January 31 to February 4, 1999. Most of the drugs presented are from the same family as drugs available today. They are said to be easier to take and, for some of them, active against viruses which are resistant to current treatments. Furthermore, new perspectives open up with T-20, a drug which blocks entry of HIV into cells.

Triple therapies without protease inhibitor
A study recently showed that Sustiva is a effective as a protease inhibitor in persons who never took any previous treatment. US experts have therefore added triple therapy with Sustiva as a first line treatment option.

Short duration trials (6 months) seem to indicate that two other triple therapies (Retrovir + Epivir + Ziagen, and Zerit + Videx + Viramune) could be as effective as triple therapies with a protease inhibitor. Trials are ongoing to confirm these results.
Triple therapies without protease inhibitor have two advantages : they are easy to take (2 times a day), and they may reduce the risks of increased blood fat levels or changes in body fat distribution which are sometimes associated to protease inhibitors.
Nevertheless, these drugs also have side-effects of their own, and not much information is available regarding these new drugs, unlike protease inhibitors, which safety and efficacy are nowadays well known.

No trespassing ! 
T-20
T-20 is the first of a new family which prevents HIV entry into cells. T-20 leads to a marked decrease in viral load, including in persons infected with a virus resistant to other drugs. Nevertheless, there seems to be a possibility for viruses resistant to T-20 to appear if the drug is given alone. T-20 cannot be given orally (by mouth), but it can be injected sub-cutaneously (under the skin surface), twice a day. These injections can easily be done by the patient him/herself. This drug is currently only available in the US, through clinical trials.

ABT 378, a new protease inhibitor.
Early trials show that ABT 378 (Abbott Laboratories) is well tolerated. It should be taken twice a day, during meals or not. Capsules also contain low doses of ritonavir (Norvir), which help increase and stabilize ABT 378 blood levels. ABT 378 is currently in clinical trials in the US ; we hope that it will be available in France end of 1999. It is planned to develop a formulation adapted to children.

Treatments with 2 protease inhibitors
For protease inhibitors to have the best possible efficacy and limit the risk of appearance of resistant viruses, these drugs need to be constantly present in blood, at levels sufficient to block HIV multiplication.
Associating two protease inhibitors sometimes enables getting higher and steadier blood levels. It also enables limiting the number of daily doses. Several associations have been studied :

• treatments using both Norvir and Invirase (or Fortovase) are now well known. Low doses of Norvir (one capsule or its equivalent in oral suspension - in the morning and evening) only serves to increase saquinavir’s efficacy. If higher doses of Norvir are prescribed (four capsules in the morning and in the evening), it is possible that Norvir’s efficacy would supplement that of Invirase. These treatments should be taken twice a day, with meals.
• Short-term studies have looked at the Norvir + Crixivan association, which enables two daily doses instead of three. Low doses of Norvir (one capsule or its equivalent in oral suspension - in the morning and evening) only serve to increase Crixivan’s efficacy. 

It may be possible to take this treatment during meals ; this is being studied. If higher doses of Norvir are prescribed (four capsules in the morning and in the evening), it is possible that Norvir’s efficacy would supplement that of Crixivan. In this case, it has been shown that treatment could be taken during meals.

Among other associations under investigation, several are of interest to improve blood levels (but their anti-HIV efficacy has not yet been properly established) : Viracept + Invirase (or Fortovase) ; Viracept + Crixivan ; Viracept + Norvir (this latter association is related with a high risk of diarrhea).

Drugs active against resistant viruses
Several drugs are being developed which seem to be effective against viruses resistant to current treatments. These drugs have mainly been studied in the laboratory and are starting to be tested in man. They could be available in 2000 :

• protease inhibitors AG 1776 (Agouron Laboratories) and tipranavir (Pharmacia Upjohn Laboratories) should theoretically be effective against all viruses resistant to other protease inhibitors;
• non-nucleosidic drugs (Sustiva, Viramune, Rescriptor) DMP 961 and 963 (Du Pont Pharma Laboratories), AG 1549 (Agouron Laboratories), MKC 442 (Triangle Laboratories) should theoretically be effective against some viruses resistant to drugs from the same family.

Crixivan
A second study confirmed that Crixivan is more effective when taken every 8 hours than when taken every 12 hours. However, some persons experience major difficulties to comply with an 8 hours schedule. They should discuss with their doctor the possibility of associating Norvir and Crixivan to only need two doses a day (see Treatments with two protease inhibitors). Furthermore, a liquid Crixivan formulation (for children) is being studied and should be available in France early 2000.

Protease inhibitors and non-nucleosidic drugs
Non-nucleosidic drugs (Viramune, Sustiva, Rescriptor) can be associated with protease inhibitors as shown by several studies. These treatments are of interest for persons for whom "classical" triple therapy is not sufficiently effective.
However, particular attention needs to be paid to drug interactions. Usually, protease inhibitors blood levels are modified (while those of non-nucleosidic drugs are not, or barely, modified). Doctors can obtain detailed information from the makers of non-nucleosidic drugs

Transmission of resistant viruses
Increasing numbers of recently contaminated persons, who were never treated, are infected with viruses resistant to one or more drugs. Resistant viruses can be transmitted through unprotected sexual intercourse, through injection material or from carrier mother to the child.

Kaposi’s sarcoma (KS)
Thanks to the progresses of anti-HIV treatments, this affection is less and less frequent, and, when it occurs, it is often kept under control. However, in some patients, KS remains a major problem. KS is due to several factors, including HHV8, a virus which plays an important part. This virus is probably sexually transmitted (especially during mouth-to-anus contacts). In the US, Doxil (Dox-SL in France) is often prescribed as first line treatment in case of severe KS (or KS affecting inner parts of the body such as the gut, lungs, etc.).
This is a drug (doxorubicine), wrapped up into microscopic bubbles called liposomes which improve its efficacy and safety.
When Dox-SL or drugs of the same family (such as the standard "ABV" (Adriamycine Bleomycine Vinblastine) chemotherapy) are not sufficient, Paclitaxel is often effective.
Other drugs have been under investigation for some time (retinoic acid, , thalidomide, HCG, etc.) but their efficacy appears often limited. Interleukin 12, for which trials are starting appears to be more interesting. Lastly, treatment with alpha interferon remains interesting for persons with more than 200 CD4.

Prevention of opportunistic infections 
Several studies have shown that treatments for the prevention of opportunistic infections can be discontinued when CD4 counts have increased, thanks to anti-HIV treatment. However, several conditions need to be met to limit the risk of an opportunistic infection occurring or reappearing :

• wait for at least 1 to 2 months after staring anti-HIV treatment;
• CD4 count needs to be above the threshold below which the risk of opportunistic infection is increased (for instance, above 100 CD4 for CMV retinitis; over 200 to 250 CD4 for Pneumocystis Carinii Pneumonia) ;
• viral load should be undetectable;
• when preventative treatment is stopped, close medical follow-up is necessary to avoid infection starting up. This is especially necessary in persons who have had a CMV retinitis episode : an eye examination needs to be performed quickly after stopping preventative treatment, even if CD4 count has markedly increased;
• when viral load remains detectable, restored immunity is usually less effective and less durable. Under these circumstances, discontinuation of preventative treatment can nevertheless be considered if CD4 count has markedly increased, with a very close medical follow-up.

Pregnant HIV carrier women :
A French study has shown that Retrovir + Epivir reduces the risk of HIV transmission to the child more than Retrovir alone : transmission risk is 2.6 % with Retrovir + Epivir, versus 6 to 8 % with Retrovir alone (and 15 to 25 % in the absence of a treatment).
Nevertheless, during this study which involved 200 newborns, two non-HIV infected children developed a rare and serious neurological disease. This disease started developing around the age of 4 months and lead to the death of the children. Additional studies are under way to determine whether this illness is related with anti-HIV drugs taken by the mothers during their pregnancy and by the children during their first weeks of life. Nevertheless, the benefits of anti-HIV treatment for pregnant women are not questioned since treatment markedly reduces the risk of HIV transmission to the child (see Remaides # 28).

Thierry PRESTEL