On the Road with Protease Inhibitors

About 12,000 people will be traveling to Geneva for the 12th World AIDS Conference in June-July, including many with HIV. Thousands of HIV-positive tourists will make other long-distance trips this summer. The time-zone changes they encounter will force adjustments in their medication schedules. The timing of taking protease inhibitors is particularly tricky. Planning ahead should reduce last minute anxiety and prevent over- or under-dosing while abroad.

Traveling with Ritonavir

Of the currently available protease inhibitors, ritonavir (Norvir) is the only one that is labeled for bid (twice-a-day) dosing. The combination of ritonavir and saquinavir (Invirase or Fortovase) is also being studied and administered on a bid schedule. Bid drugs need to be taken at two reasonably spaced intervals during the day. A bid regimen allows some leeway in the dosing schedule. Given the rate at which the body eliminates bid drugs, there is a window of about two to three hours, so doses can be taken 9 to 15 hours apart. However, because of the wide variation in plasma drug levels in individuals taking protease inhibitors, it is safest to stick as closely as possible to 12-hour dosing intervals even on a bid regimen.

When traveling overseas, various factors need to be taken into consideration such as the time and length of the flight and the time difference between the city of origin and the final destination. For example, Geneva is six hours ahead of Eastern Standard Time (EST). Most European flights from the New York area are in the evening and flying time is about seven hours. On a bid regimen, the evening dose should be taken one hour before the flight. When breakfast is served on the plane the following morning, the first dose of the day is taken, even though by elapsed time it is only eight hours since the last dose. Because of the time difference it will be mid-morning upon arrival in Geneva. Ten hours later the evening dose is taken at about 8:00 p.m. Geneva time. The next day, the morning dose is taken 12 hours later with breakfast, bringing the schedule back on track.

In this scenario, no doses are missed. In fact, because there are actually fewer hours in the day when first crossing into a European time zone, two doses are taken closer together and then adjusted back to 12-hour intervals (eight hours between doses then ten hours then back to 12 hours). This might cause a temporary increase in side effects, although it is unlikely. Midwestern or West Coast travelers with longer flight times and larger time differences can make similar adjustments.

The hours lost when traveling to Europe are regained when returning. The day of travel is more than 24 hours long because the clock is set backwards when returning to the U.S. It is important to observe the actual time elapsed from departure rather than the clock, or a dose could be missed. The morning dose occurs in Geneva on the day of departure. Because of the time difference, an afternoon flight from Geneva will arrive on the East Coast that same afternoon EST although it will be the evening by Geneva time. The second dose should be taken towards the end of the flight. The airline may not be serving a meal at this time, so it is prudent to have food on hand with a fat content sufficient to aid drug absorption. The next dose can be taken that evening before going to bed. On this day, three instead of two doses will be taken (one in Geneva in the morning, one on the plane and an extra one in the evening). The extra dose covers the six hours gained in transit to insure that the plasma drug concentrations do not fall below the level required for suppressing HIV. The next morning the regular schedule resumes with breakfast. Again, this system can be adjusted for flights to other destinations (see table I).

Table I: Adjusting a Bid Regimen for Overseas Travel
Departing for Europe	Returning to the U.S.
Evening dose 8 hours prior to arrival in Geneva	Morning dose prior to flight
Morning dose upon arrival	Evening dose on plane 8 hours later
Evening dose 10 hours later	Another dose prior to bed 10 hours later
Morning dose 12 hours later	Morning dose 12 hours later
Resume normal schedule	Resume normal schedule

Keep Indinavir Doses Exactly Eight Hours Apart

Modifying an indinavir (Crixivan) dosing regimen is not a good idea because it is administered on a strict eight-hour basis (q8h). According to representatives at Merck, it is best not to take extra doses of the drug to avoid potential side effects such as kidney stones. The company recommends staying on the U.S. schedule, with only slight adjustments made when absolutely necessary. A sample q8h dosing regimen is 7:00 a.m., 3:00 p.m. and 11:00 p.m. (EST). This translates to Geneva time as 1:00 p.m., 9:00 p.m. and 5:00 a.m. On the day of departure, all doses are taken according to U.S. time. For a night flight, the first and second doses can be taken prior to take-off and the third dose can be taken on the plane at 11:00 p.m. EST.

The schedule is translated into local time upon arrival. The first dose should be taken at 1:00 p.m. Geneva time -- this corresponds to the morning dose. The "afternoon" dose is then taken at 9:00 p.m. Geneva time. The third dose, corresponding to the evening dose, is actually taken at 5:00 a.m. the next day (if possible set the alarm clock to take the 5:00 a.m. dose at that time). Only two doses are taken on the day of arrival in Geneva but no dose is missed because the day has fewer hours due to the time difference. Things even out on the day of return to the U.S. when the lost time is regained and four doses of indinavir are taken -- see table II.

Table II: Translating the Indinavir Schedule
Departing for Europe	Returning to the U.S.
As usual every 8 hours on day of departure, 3rd dose of the day probably in flight	In the European routine the 3rd dose of the day is taken the morning of the next day. Take this dose before the flight.
1st dose on European time will be in the afternoon, 8 hours after last dose on plane (this equates with the U.S. a.m. dose)	1st dose 8 hours later, probably during the flight
2nd dose taken that evening, 8 hours later (this equates with the U.S. afternoon dose)	2nd dose 8 hours later, this will be back on U.S. time in the afternoon
3rd dose taken the following morning, 8 hours later (this equates with the U.S. p.m. dose)	3rd dose resumes its normal position that evening, 8 hours later
Maintain new routine	Maintain U.S. schedule

When returning to the U.S., travelers take the 5:00 a.m. dose on the day of departure. The next dose will occur at the airport or on the plane at 1:00 p.m. Eight hours later, when it is time for the third dose, the traveler will have crossed back into the U.S. time zone and regained the hours lost when going abroad. So, the third dose on the return date will be taken at 3:00 p.m. EST instead of 9:00 p.m. Geneva time. Eight hours later, the evening dose has resumed its normal position at 11:00 p.m. EST. In this way, the schedule has come full circle without any increases or decreases in dosing frequency and blood concentrations. The next morning, the regular U.S. routine resumes at 7:00 a.m. (If the dosing was pushed up by one or two hours in Geneva to make the schedule more convenient, it can gradually be returned to normal by decreasing the interval to 7 1/2 hours between the evening and morning doses over two to four days. This should minimize the risk of side effects.)

Nelfinavir and Saquinavir Allow Some Flexibility

There is a difference between strict eight-hour dosing and the less restrictive three times a day dosing (tid). While indinavir is administered q8h, nelfinavir (Viracept) and saquinavir are tid drugs. According to company studies, nelfinavir can be dosed 6 to 11 hours apart without increasing side effects or decreasing drug levels below the minimum required amount. Similar studies have found that the interval between saquinavir doses can reach ten hours with only a small impact on drug levels. Nelfinavir and saquinavir are more stable in the body and do not exhibit the large fluctuations in peak and trough levels seen with indinavir.

The method of directly converting the U.S. dosing schedule to European time can be accomplished in the same way as for indinavir in table II. This is not strictly necessary, though, because there is more leeway with the dosing intervals of nelfinavir and saquinavir. Also, whereas indinavir needs to be taken on an empty or nearly empty stomach, nelfinavir and saquinavir require food and should be coordinated with meal times if possible.

For those on tid regimens, the following scenario might be feasible. On the day of departure, all three doses can be taken on the U.S. schedule, including the evening dose that will probably be taken in-flight. Upon arrival in Geneva the following morning, the doses can be adjusted to three evenly spaced intervals, as long as they are between six and ten hours apart. This schedule can be modified over the course of one or two days until it fits in conveniently with daily activities. As long as doses are not missed or taken too far apart, the tid regimen is fairly flexible. When returning to the U.S., one dose should be added to make up for the time gained in travel (see table III).

Table III: Nelfinavir and Saquinavir Dosing Abroad
Departing for Europe	Returning to the U.S.
As usual every 8 hours on day of departure	On day of return add 1 dose to make up for time gained in flight
Adjust doses upon arrival in Geneva to 3 evenly spaced intervals	Resume normal schedule day after return

Other Factors to Consider Ahead of Time

Ritonavir needs to be refrigerated. Fortovase, in principle, can safely remain at room temperature for 90 days, but the capsules melt, so refrigeration is necessary in hot summer weather. Request a room with a refrigerator when making hotel reservations. Transport drugs in coolers or insulated bags with ice packs.

Indinavir users need to drink at least eight large glasses of water per day and should plan to carry safe bottled water. It is especially important to maintain the intake of fluids in flight. Additionally, indinavir is packaged with a desiccant that keeps the drug stable. This should also be transferred with the indinavir to any other containers. (It is wise, though, to carry all medications in their original prescription bottles to avoid problems with Customs.)

Indinavir can be taken on an empty stomach or with a light meal or snack (two or less grams of fat and 5.7 or less grams of protein). Merck has compiled a list of foods that can be taken with indinavir; call 888/CRIXIVAN for information. For saquinavir or ritonavir, recent consumption of 15 to 30 grams of fat is necessary to facilitate absorption. Nelfinavir should also be taken with food. Agouron Pharmaceuticals recommends taking nelfinavir with a snack or light meal larger than one fruit or vegetable. Bringing food on the plane is a good idea, as airline snacks may not be adequate.

Beepers, timers or programmable pillboxes may help remind travelers of an unfamiliar dosing schedule. Carrying a second watch that remains on U.S. time may be helpful, too. It is advisable to pack an extra supply of medication in case pills are lost.

Finally, the dosing of concomitant medication needs to be coordinated with the new protease inhibitor schedule. Adjustments are required in some cases to avoid drug-drug interactions. For example, ddI and indinavir are both taken on an empty stomach at least two hours apart. First determine the European indinavir routine and then fit in the ddI doses at suitable times. Most of the other nucleoside and non-nucleoside analogs are prescribed bid with no food restrictions and can be taken along with the morning and evening protease inhibitor doses.

These suggestions are not a substitute for medical advice. All individuals have their own particular issues, regimens and schedules and should consult their own physicians about specific travel plans.