Hepatitis and Malaria Update

Conference Coverage
By Mary-Louise Scully, MD

Recent Advances in Travel Medicine: New Products for the Prevention of Hepatitis A and B and Malaria in Travelers

This symposium was held in conjunction with the recent American Society of Tropical Medicine and Hygiene (ASTMH) Annual Meeting in Atlanta, Ga. The first segment of the program covered several new and important developments on the topic of hepatitis in travelers, and the remainder of the evening provided an update on malaria prevention.

Alan Spira reviewed the clinical aspects and risk factors for acquisition of hepatitis A (HAV) and hepatitis B (HBV) infection. Physicians’ advice to travelers should always include food and water precautions for prevention of HAV and avoidance of blood and bodily fluid contact for HBV. However, unexpected exposures from events such as accidents, illnesses requiring medical care, and unprotected sex can occur during travel. Therefore, in addition to exposure prevention, all at-risk travelers should be vaccinated.

Jay Keystone discussed the currently available monovalent hepatitis A and B vaccines and the combination hepatitis A and B vaccine, Twinrix, which has recently been approved. A 1-mL unit dose contains 720 ELISA units of inactivated HAV and 20 mg of recombinant HBsAg protein. It is recommended for all susceptible persons 18 years or older who are at risk of exposure to HAV or HBV. The dosing schedule is 0, 1, and 6 months. Results of controlled studies demonstrate similar immunogenicity profiles for the combination vaccine and monovalent vaccines: the combination and monovalent vaccines each induced seroconversion to HAV in 99% of subjects, while for HBsAg, the seroconversion rates were 95% and 92%, respectively. The combination and monovalent vaccines had similar safety profiles, the most common adverse events being soreness at the injection site, headache, and fatigue.

As many as 40% of travelers first seek travel advice within only a few weeks of departure. In order to ensure such travelers still receive effective vaccinations, a number of accelerated schedules for HBV are in use, although not all are approved by the FDA. One such dosing schedule is 0, 7, 21 days, and 12 months. Using this schedule for combination hepatitis A and B vaccine provided greater than 80% seroprotection for HBV and 100% for HAV 1 week after the third dose.¹ In addition, an open, randomized, multicenter study of 244 adults in Germany examined the effect of interchanging between monovalent and combination vaccine formulations during the course of an immunization series and found that this approach did not alter seroconversion rates.² Therefore, patients who begin immunization with monovalent hepatitis A and B vaccines can complete the series with combination hepatitis A and B vaccine without any compromise in effectiveness.

The use of the combination vaccine will save time for doctors and their staff, reduce administration costs, and allow more efficient use of vaccine storage space. The traveler will benefit by receiving fewer total injections (3 vs 5). This has practical implications for the patient who needs multiple vaccinations for their trip.

Following the presentations, there was a panel discussion moderated by Elaine Jong, during which several issues were raised. One concerned the best approach to the patient whose HBV schedule is unintentionally interrupted. In this situation, the vaccine series should just be continued. There is no need to restart the series. The difficult issue of what to do with HBV nonresponders was also discussed. Some physicians have had success using an accelerated schedule of 0, 7, 21 intradermal HBV, or using twice the normal dose (ie, 40 mg) at a single administration. Panelists stressed the important point that the hepatitis A titer (IgG) should be used only for detecting whether a patient has natural immunity to HAV and should not be ordered to check for seroconversion after the combination or monovalent HAVs.

The topic of discussion then shifted to malaria. Kevin Kain discussed new strategies for malaria prevention. Malaria remains a significant problem with 1227 US cases reported in 1998, the most recent year for which figures are available. The predominant species was Plasmodium falciparum (Pf) with 525 cases (42.8%). The majority of these Pf cases were acquired in Africa—the highest proportion from countries in West Africa.³

Many cases of imported malaria are in individuals who return to their country of origin after long absences to visit friends and relatives (VFRs). One prospective study of VFRs leaving Canada to travel to India showed that only 54% had sought advice before traveling (more than 70% from a family doctor), only 31% intended to use any antimalarial chemoprophylaxis, and only 7% had been prescribed a recommended drug regimen. More alarming is the fact that less than 10% were planning to use any personal measures to prevent mosquito bites.⁴

The currently recommended drugs for chloroquine-resistant Pf malaria (CRPf) prophylaxis include mefloquine (MFQ), doxycycline (Doxy), chloroquine/proguanil (CP) or atovaquone/proguanil (AP). AP is now marketed as a fixed dose combination with the trade name Malarone. Each AP tablet contains 250 mg of atovaquone and 100 mg of proguanil. The pediatric tablet contains 62.5 mg atovaquone and 25 mg of proguanil. Atovaquone is a selective inhibitor of parasite mitochondrial electron transport. Proguanil’s metabolite, cycloguanil, is a dihydrofolate reductase inhibitor. Together the drugs demonstrate antimalarial synergy. AP is now approved for prophylaxis of Pf malaria including CRPf. Prophylactic treatment with AP should be started 1 or 2 days before travel to an endemic area, continued daily during the stay, and for 7 days after return. The dose should be taken at the same time each day with food or a milky drink to minimize the gastrointestinal side effects.

Three placebo-controlled studies of AP prophylaxis for Pf malaria done in Gabon, Kenya, and Zambia showed a protective efficacy of 98%.^5-7 More studies are ongoing in nonimmune persons. To date, one study comparing AP to CP and another comparing AP to MFQ suggests that AP was better tolerated than MFQ and CP, and that AP may be more effective in preventing Pf malaria than CP.^8,9

No operational resistance to AP has yet been documented. AP does have causal prophylactic activity for Pf but not for Plasmodium vivax (Pv). Therefore, if a traveler is going to be heavily exposed to Pv, Dr. Kain emphasized that a terminal course of primaquine prophylaxis should be given.

Studies using AP in pregnancy are ongoing in Thailand and Zambia, with no treatment failures to date in 26 subjects. AP is secreted in breast milk, but it is unlikely that infants exposed passively to AP during breastfeeding achieve adequate levels to provide protection. Therefore, the infant of a breastfeeding mother who is receiving AP should also be prescribed malaria prophylaxis. However, at this time, the safety and effectiveness of AP for treatment or prophylaxis of malaria in pediatric patients who weigh less than 11 kg has not been established.

No dosage adjustments are needed for the elderly or patients with mild-to-moderate renal or hepatic impairment. However, AP is contraindicated in patients with severe renal failure (CrCl less than 30 mL/min).

AP scores well in terms of efficacy, tolerability, and convenience. It has the added benefit of causal activity for Pf. However, it is relatively expensive. More data are needed on the long-term safety and tolerability of AP.

AP can be added to the recommended drug choices for malaria prophylaxis. The availability of more drug options for prophylaxis will hopefully improve patient compliance and result in a decrease in the number of cases and fatalities associated with imported malaria.

References

1. Zuckerman JN, et al. Rapid protection against hepatitis A and B following accelerated schedule of a combined hepatitis A/B vaccine (abstract). Antiviral Ther. 2000;5(suppl 1):8.

2. Kallinowski B, et al. Can monovalent hepatitis A and B vaccines be replaced by a combined hepatitis A/B vaccine during the primary immunization course? Vaccine. 2000;19:16-22.

3. Centers for Disease Control and Prevention. CDC Surveillance Summaries, December 7, 2001. MMWR Morb Mortal Wkly Rep. 2001;50(No.SS-5).

4. Dos Santos CC, et al. Survey of use of malaria prevention measures by Canadians visiting India. CMAJ. 1999;160:195-200.

5. Lell B, et al. Randomized placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet. 1998;351:709-713.

6. Shanks GD, et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis. 1998;27:494-499.

7. Sukwa TY, et al. A randomized, double blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hygiene. 1999;60:521-525.

8. Hogh B, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in nonimmune travelers: A randomized, double blind study. Lancet. 2000;356:1888-1894.

9. Overbosch D, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: Results from a randomized double blind study. Clin Infect Dis. 2001;3:1015-1021.

Published: February 2002