"Tricks to Prevent Gagging with Ritonavir Liquid" is the title of an article written by staff in Children's Hospital in Chicago who have had extensive experience in getting children to take liquid Ritonavir. atp.org.uk
"Abbot announced on July 27th that they would not be able to supply Ritonavir capsules after the middle of August due to manufacturing difficulties. Aside from the obvious inconvenience of using a liquid instead of a pill, the ritonavir oral solution is notorious for its unpleasant flavor and bitter aftertaste, which is often compared to "motor sludge." hivatis.com and healthcg.com
Abbot is substituting liquid Ritonavir, which has identical antiretroviral activity, once it gets to the stomach. That is the crux: getting to the stomach. It is easier said than done due to the terrible taste of the liquid and the aftertaste it leaves. An additional problem is the high alcohol content (43%) which can cause a burning or tingling sensation commonly felt as the ritonavir goes down the esophagus."
Treatment Issues, Volume 12, Number7/8 Ritonavir Users Put on Liquid Diet
"Although the production problem first occurred in June, Abbott waited until the end of July to inform the community, probably hoping to resolve the situation in time to avoid a shortage. In early June ritonavir crystals started turning up in Ritonavir capsules. These crystals lowered the bioavailability causing inadequate levels to be absorbed. Because Abbot does not know the source of the problem they do not know when it will be fixed."
"Unfortunately, by the time Abbott made its announcement, there was less than a month's worth of capsules left. On the retail level, pharmacies scrambled to manage supply and demand. At least one major drug store in New York City reported limited quantities of both capsules and liquid by the first week of August and was rationing out seven-day allotments of the drug. Abbott is increasing production of the oral formulation so that by the time pharmacies completely run out of the capsules, there should be enough liquid to meet the demand. "
Treatment Issues, Volume 12, Number7/8 Ritonavir Users Put on Liquid Diet
It is disturbing (to me, at least) to note that Abbot did not mention these production problems at Geneva and issued a glowing press release on June 30th:
"World AIDS Conference Data Supports Dual Protease Inhibitor Therapy with Norvir as First-Line Treatment for HIV and AIDS"
This press release stressed the tolerability and durability of the Rit/Saq regimen, using terms such as tolerability, convenience, convenient etc 12 times. biz.yahoo.com
More new patients were probably put on Ritonavir as a result of Abbots presentations at Geneva. I do remember that there were glowing reports in the WSJ and thestreet.com, of course, commenting on what a great impression Abbot's Ritonavir made on many physicians at Geneva. Maybe Abbot thought they would have fixed the problem by then, but they could have mentioned it. Ritonavir was first approved as a protease inhibitor in the liquid formulation and it was know then how terrible the taste was. The capsules were introduced later. Then there was no choice. Now there is, at least for new patients.
It's different for patients already on Ritonavir or Ritonavir/Saquinavir who are successfully keeping their viral loads undetectable. They would be better off trying to tolerate the liquid, then switching to a completely different regimen. "Some people will be able to switch to the liquid until Abbott resolves the problem. There will also be those who are unable to make the necessary adjustments to an already difficult treatment regimen and who will have to find other options."
healthcg.com
It is difficult to imagine that physicians will put new patients on Ritonavir liquid knowing about the tolerability problems associated with the liquid, unless they are not aware of them. Then again, not too much surprises me anymore... And it is unclear how long this interruption will last and there are concerns that patients who cannot tolerate the "taste" of the liquid form of Ritonavir may be switched to regimens that are cross resistant to what they are on. Worldwide there are about 65,000 people on Ritonavir and not all are cared for by HIV experts, and even the experts are not in agreement as to the best course of action. An article by Dr. Calvin Cohen discusses the difficulties and decisions that patients and physicians will face.
Lack of adherence is reported to be one of the major causes of failure on anti-retroviral therapy and this will add to the difficulty. As far as the "tricks" the idea is to overpower the taste buds with a flavor and coat them before taking ritonavir. Some suggestions include using a straw to suck the liquid straight to the back of the throat. Some centers are also recommending the use of dosing syringes to squirt the liquid directly to the back of the throat, bypassing the taste buds."
In order to improve the taste, Abbott suggests mixing ritonavir liquid with chocolate milk, Advera or Ensure (two nutritional supplements, the latter manufactured by Abbott). The bioavailability of the ritonavir oral solution is unaffected by these three beverages (R. Bertz et al. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Sept. 1996; Abstract A25).
Since the liquid has always been used in pediatrics, many ideas have been explored to make the flavor more palatable for children. The federal Guidelines for Antiretroviral Use in Pediatric HIV Infection suggest:
** Mixing the oral solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream.
** Dulling the taste buds prior to dosing by chewing ice or sucking popsicles.
** Coating the mouth by giving peanut butter first.
** Administering strong-flavored foods such as maple syrup, cheese or gum (one pediatric nurse suggested Bubble Yum) immediately after the dose.
Other ideas include taking ritonavir liquid with yogurt or Kool Aid. It may be best to take food or drink before and after the dose to disguise the flavor and aftertaste as much as possible.
The dual protease inhibitor combination of Ritonavir/Saquinavir is used more widely than either PI alone, as this combination allows lower dosing of both PI's which results in less side effects and a more tolerable regimen. Currently both are given at 400 mg twice daily. Ritonavir is a strong inducer of P-450, this slows the metabolism of certain Fortovase and increases the strength of Fortovase 20 fold. Because of Abbot's production problems, patients may drop the Ritonavir if they cannot tolerate it, and take only Fortovase, but the combination of the two PI's is thought to be more potent, and Fortovase taken alone requires taking 18 large oil-coated capsules a day.
Note that while Abbot's June 30 press release commented about similar discontinuation rates for indinavir vs ritonavir/saquivnavir, they neglect to mention the discontinuation rate for ritonavir. I wonder why???? I don't have time to look it up, but with 58% on Crixivan vs 39% on Ritonavir BQL <20 copies at 1 year, it would not be too surprising if there were significantly more dropouts on Ritonavir.
<<< At one year, the proportion of patients in the antiretroviral naive group achieving an HIV-RNA of less than 20 copies per microlitre was 77 per cent in the ritonavir/saquinavir group compared to 58 per cent in the indinavir group and 39 per cent in the ritonavir-only groups. There were no differences in the discontinuation rate between patients on indinavir and patients on ritonavir/saquinavir.>>>
BTW, 48 week data was presented at Geneva, for Fortovase +2 nucleosides. The soft gel version permits 8 times more exposure than the original HGC. But there are more side effects as it is more potent. Of interest, at 16 weeks, 17/90 or 19% had dropped out and 24/90 or 26% had withdrawn prematurely at 48 weeks.
The percent of patients BLQ <400 copies and <50 copies was 57% and 51% respectively, using Intent to Treat, but it doesn't specify which Intent to Treat: if it was LOCF or NC=F. It makes a difference.
The increase in CD4 was~160. Maximum suppression occurred at 40 weeks and then looked liked it flattened out or declined slightly.
iapac.org
Ritonavir has the most side effects of all the protease inhibitors, the highest dropout rates, the most drug interactions, and is thought to have the highest incidence of lipodystrophy. Actually the dual combination of ritonavir-saquinavir may have a higher incidence.. Crixivan is a close second, as far as side effects and dropout/withdrawal rates. Clearly, there is a link between non-adherence and increased viral load. Thus, mechanisms to improve compliance are a crucial component of any antiretroviral regimen...
Discontinuation Rates of various Protease Inbibitors.
Reiter* reported discont.. rates of 20-23% for Ritonavir (Ritonavir study 245,247)
Reiter* reported discont.. rates of 12-13% for indinavir (ACTG Study 320, 867)
Reiter* reported discont. .rates of 4% for Nelfinavir (Viracept) in trials 505, 506, 511.
The Fortovase discont. rate above was 26% in the above study. .
The Efavirenz (Sustiva) discont.rate was 20.6% in Dupont 006
*Low rate of nelfinavir discontinuation in a clinic population.Reiter, Wojnarowski.
Abstract 60273-Geneva.
Many wonder why Dupont's study 006 showed such high discontinuation rates for crixivan - 38%. One reason given is that Sustiva was given once a day (three pills) and Crixivan was given in 200 mg doses (5 pills 3 times a day, although 400 mg doses are available. And the trials were open, so those in the Crix arm knew the others were getting a lot less pills. The high discontinuation rate for crixivan makes results in an Intent to Treat analysis a lot worse.
Sooooo, of all the protease inhibitors, Ritonavir has the most side effects, most drug interactions, highest discontinuation rates and Viracept appears to have the least side effects, lowest discontinuation rates, and is the most tolerable. Sustiva, the nonnuke that caused such a stir at Geneva, has more side effects and a much higher dropout rate than Viracept and most of the PI's, and the decrease in viral load, which is the real gold standard, does not appear to be as durable as occurs with protease inhibitors. There already are comments, still anecdotal, that report that lipodystrophy occurs with Sustiva as well. Sustiva is not as tolerable as it is being made out to be, especially in terms of "altered mental status." The 20.6% dropout rate at 24 weeks reported by Dupont should indicate something.
Note these comments from Doctor Fax 51: at.org.uk
<<Data on NNRTI's needed to reassure of equivalency to PI's include issues of immune function (does the immune system recover qualitatively on NNRTI's as has been seen with PI's?). Is immune restoration as rapid and will lymph node clearance be seen? ** Additionally, long-term toxicity data is needed; PI's were assumed to be safe and relatively non-toxic at a similar stage in the game. Will we be looking for NNRTI-sparing regimens in 3 years time due to unforeseen longer-term toxicitys? >>
**Jules Levy reported a study from Geneva in the NATAP site showing better clearance from the lymph nodes on a PI regimen than on an NNRTI regimen.
And probably the most important point that someone forgot to point out:
Combining a protease inhibitor with a non-nuke and one or two nukes or combining a PI plus a NRTI plus a NRTI plus hydroxyurea has given better results than any regimen with just one NNRTI and two nukes, as far as reducing the viral load and increasing the CD4 counts.
|
