| Four new anti-HIV drugs: Agénérase, Ziagen, Sustiva, Prévéon | |
Agénérase (amprenavir): a new protease inhibitor
Dosing Agénérase (amprenavir) is available as large 150 mg capsules. The manufacturer is working on a 50 mg capsule for children. A liquid formulation also exists, but it is only available through an ongoing clinical trial. Agénérase should be taken twice a day (for adults : 8 large capsules twice a day), with no restrictions regarding timing of meals. Efficacy, side-effects First results suggest an efficacy and a rate of side-effects similar to that of other protease inhibitors. It seems to be better tolerated than Norvir but it can also cause tingling sensations in the mouth (paresthesia). Nausea, vomiting, diarrhoea and skin rashes (spots, red rashes) have been observed in various trials. Severe skin problems, related with allergy to Agénérase, are very rare. It is too early to know whether, as other protease inhibitors, Agénérase leads, in some patients, to increased fat levels in blood and changes in the distribution of body fat (see Remaides n° 29). Resistance Agénérase might, in some cases, be active against viruses which resist to other protease inhibitors; trials to document this are ongoing. Interactions Drug interactions seem close to those of Crixivan (some tranquillisers and sleep inducers are contra-indicated, some antibiotics dosages need adjusting, etc.). Sustiva and rifampin (an anti-tuberculosis drug) markedly reduce Agénérase blood levels, and Agénérase increases Retrovir blood levels. Waiting for the second generation Because of the number and size of capsules required, the existence of side effects and of drug interactions, Agénérase can be considered as a first generation protease inhibitor. It is nevertheless one more option for patients. Ziagen (abacavir): Efficacy
Its manufacturer, Glaxo Wellcome, has compared double combination therapy (Retrovir + Epivir) to triple therapy (Retrovir, Epivir, Ziagen). Obviously enough the trial shows that triple therapy is better than double therapy ! Other, very preliminary results, show that, in people who never took any treatment, triple therapy (Retrovir, Epivir, Ziagen) could be nearly as efficacious as Retrovir, Epivir, Crixivan. Dosage One 300 mg tablet in the morning and in the evening, with no restrictions regarding timing of meals. A liquid formulation for children is available. Resistance it seems that a virus resisting to the other nucleosides (see The four families) is often, but not always, less susceptible to Ziagen (with the exception of a virus which is only resistant to Epivir). Side effects Ziagen can lead to allergic reactions, appearing on average ten days after starting treatment and usually characterised by general malaise with fever (similar to flu). If this occurs, quickly inform your doctor. In case of major allergic reaction to Ziagen, this drugs needs to be stopped and avoided in the future, to avoid causing extremely severe allergy which can lead to death. Availability Ziagen is available in France within "ATU de cohorte" (your doctor needs to call Glaxo Wellcome at 0 800 50 57 54), or "ATU nominative" if one does not meet requirements for "ATU de cohorte". Abacavir as a liquid solution for children is also available through "ATU nominative". Sustiva (efavirenz): very fashionable Sustiva (efavirenz) belongs to the same family as Viramune and Rescriptor (see Remaides n° 28, p. 26). Dosage
Efficacy A 36-week trial has shown that, in people who never took any treatment, triple therapy with Retrovir, Epivir and Sustiva appear as effective as triple therapy with a protease inhibitor (Retrovir, Epivir, Crixivan). This trial is still going on to assess long term effects. Side effects For unknown reasons, Sustiva leads to temporary disturbances in over half the patients : vertigo, feeling of drunkenness, sleep disturbances, anxiety Very rare cases of depression or hallucinations have been reported. Your doctor should inform you about this and will advise taking Sustiva in the evening. These effects usually occur very quickly (as early as the first or second dose), and subside over time (after roughly 2 to 3 weeks). However, some cases of such side effects (sleep disturbances, anxiety) persisting for several months have been reported. This has not yet been scientifically studied : Sustiva's medium and long term side effects on the nervous system are not known. Furthermore, like its "relatives" Viramune and Rescriptor, Sustiva can be associated with skin rashes or red spots in the days or weeks after starting treatment. If this occurs, your doctor should be quickly informed of this, even though this side effect is usually not serious and disappears spontaneously. Drug interactions Sustiva lowers other drugs' blood levels such as Invirase or Fortovase and, possibly Agénérase, and decreases their efficacy. Crixivan doses should be increased from 800 mg to 1000 mg. Norvir or Viracept doses do not need adjusting. Sustiva can also affect blood levels of some antibiotics and antifungal drugs : prepare a list of all drugs you may need to take, and talk to your doctor. Resistance They appear to be similar for Viramune, Rescriptor, Sustiva. A virus resisting to one of these drugs will often resist to the other ones. However, at times, a virus resistant to Viramune may be sensitive to Sustiva. To be continued Availability Sustiva is widely available in France since May, through the "ATU de cohorte" system (doctors need to call Dupont Pharma at 0 800 87 93 19). It is available through the "ATU nominative" system for children (doctors need to call the Agence du Médicament at 01 55 87 30 00). Sustiva should promptly obtain its marketing approval in France. Conclusion Sustiva appears to be a very interesting new drug. Some doctors already prescribe it as first line treatment within a triple therapy (with no protease inhibitor). Will this strategy be included in the next official French guidelines? Prévéon (adefovir dipivoxil), the fourth element
This is tiny ! Prévéon optimal dosage is not yet clearly finalised : it will be 60 mg, once a day (tablets are tiny), with no restrictions regarding timing of meals. Efficacy Prévéon's efficacy, although limited, has been demonstrated. In people who never received treatment, Prévéon leads to lower viral loads, although somewhat less so than Retrovir. Side effects Major kidney toxicity was seen in approximately one third of patients after 6 months of treatment. However, kidneys seem to work normally once treatment is stopped. To decrease this toxicity, Prévéon's dosage has been reduced from 120 mg to 60 mg daily. Blood tests performed on a regular basis should enable detecting this kidney toxicity before it becomes too severe. In addition, Prévéon leads to a deficiency in carnitine, an amino acid necessary to the body. To avoid any problem, two 500 mg carnitine tablets a day should be taken (they are provided with Prévéon). Resistances First results are disappointing and complicated. If one is infected with an HIV highly resistant to Retrovir, Prévéon is not very effective. On the other hand, against an HIV highly resistant to Epivir, Prévéon seems to be twice more efficacious than against a non-resistant virus. Finally, Prévéon's efficacy against a virus which is resistant to Retrovir and Epivir seems similar to its efficacy against a non-resistant virus. Availability Available in the US for over a year, Prévéon should soon be available in France. Doctors need to ask for an "ATU nominative" (see above). Prévéon is made by Gilead. What to do with it ? Its weak efficacy and its kidney toxicity make it a difficult drug to use against HIV. However, it may be more interesting against hepatitis B, where lower doses (30 mg a day) are used. In addition Gilead are studying a second drug from the same family : PMPA. The very first trials with PMPA suggest a much higher anti-HIV efficacy. Emmanuel Trenado
The four families (please note : all trade names are the ones used in France) Inhibitors of reverse transcriptase - nucleosides : Retrovir (AZT), Videx (ddI), Hivid (ddC), Zérit (D4T), Epivir (3TC), Ziagen (abacavir), Combivir (a 3TC and AZT combination) - non-nucleosides : Viramune (nevirapine), Rescriptor (delavirdine), Sustiva (efavirenz), and soon MKC 442. - nucleotides: Prévéon (adefovir dipivoxil) and soon PMPA. Protease inhibitors Invirase (saquinavir), Fortovase (saquinavir), Crixivan (indinavir), Norvir (ritonavir), Viracept (nelfinavir), Agénérase (amprenavir).
Interactions : how to know more A table of drug interactions is regularly updated on the Internet site of the Johns Hopkins University : https://www.hopkins-aids.edu/treatment/index_treat.html or on the University of Liverpool site : https://www.liv.ac.uk/hivgroup On Sustiva, you may also look up: | |
This drug is available in the USA since October and
in France since mid-November. To obtain it, your doctor needs to request
a named-patient "ATU" (Autorisation Temporaire d'Utilisation nominative)
from the Agence du Médicament (phone 01 55 87 30 00). An "ATU
de cohorte" system should soon be available, which will make the drug
easier to obtain (directly from Glaxo Wellcome).
Ziagen (abacavir) appears to be the most powerful drug of the nucleoside
family (Retrovir, Videx, etc. See The four families). Used alone, Ziagen
leads to decreases in viral load two to three times higher than other nucleosides.
One single daily dose of three 200 mg capsules, preferably in the evening
to minimize side effects. It can also be taken twice a day, for instance
2 capsules in the evening and one in the morning or at lunch time : some
people tolerate it better this way. There are no restrictions regarding
timing of meals, however, the meal closest to the Sustiva dose must not
contain too much fat, otherwise there is a risk of increasing Sustiva absorption
(which is already very good) and worsen side effects. 100 mg capsules are
also available ; 50 mg capsules will soon be available. Dupont Pharma, the
manufacturers, prepare a 600 mg capsule for next year.
Prévéon (adefovir dipivoxil) is the first
of a new anti-HIV drugs family (see The four families). It is active against
HIV, but also against Hepatitis B and, at least in the lab, against CMV.