Response to Vaccination

Hepatitis B vaccination continues to be the best available means of preventing and controlling hepatitis B infection. Current recombinant hepatitis B vaccines achieve seroprotection in greater than 95% of the vaccinated adult population (172). However, approximately 5% of the adults respond inadequately to the standard three doses of hepatitis B vaccine. Those adults who have an antihepatitis B (anti-HBs) titer of less than 10 mIU/mL are defined as poor- and nonresponders. The lack of anti-HBs antibody response has been attributed to many factors and these include improper storage, advanced age, gender, obesity, renal failure, and smoking (172,173). In addition, genetic factors, specifically the histocompat-ibility leucocyte antigens (HLA)-linked immune response genes may control the response to hepatitis B vaccine, and a poor antibody response is associated with certain HLA hap-lotypes. Earlier studies have found that immune response to hepatitis B vaccine is largely determined by the HLA-DR, -DP, and -DQ genes. Specifically haplotypes DRB1*1101, and -DQB1 *020 were associated with poor responsiveness. There were also interactions between the HLA factors contributing to poor responsiveness. For example, HLA-DPB1 *02 was negatively associated with responsiveness when it occurred in association with haplotypes DRB1 *0701 /DRB4 *0101-DQB1*020*, and DRB4 *0101 was negatively associated with responsiveness when it occurred in association with the haplotype DRB1 *0301/DRB3*0101-DQB1*020* (174).

More recent studies have shown that different HLA products seem to act as agonists (C4AQ0 and HLA-DQB1*02) or antagonists (C4AQ0, HLA-DQB1*02, and HLA-DRB1 *11, DQB1*0301) in lowering the humoral response to hepatitis B vaccine (175). It was found that responders were characterized more for lacking "nonresponder" alleles than for having specific "responder" ones. Investigations into the associations of HLA alleles and antibody nonresponse in the Caucasian population have also identified other HLA -genotypes including C4A3, B44, DR7, FC31, B8, DR3, and SC01 (176-178). Because genes present in the major histocompatibility complex modulate the immune response to hepatitis B vaccine, poor- and nonresponders may benefit from a course of revaccination (176). In fact one study showed that revaccination could enable persistently nonresponder individuals to produce an anti-HBs antibody response; however, the response was dependent on HLA haplotype and the dose of vaccine (179).

VALIDATION OF PHARMACOGENETIC MARKERS

The treatment of diseases, such as TB, malaria, and HIV, is highly standardized and would thus allow acquisition of genetic information at a rapid pace. Similarly, the abundance of clinical trials in infectious diseases could contribute to a critical resource of response and toxicity data. In clinical trials, genotype can be used as an exclusion criterion (180,181). Thus, the study group can be smaller and more homogeneous, although less representative of the population at large. This approach would be of particular interest in the study of sepsis, given the great heterogeneity of the syndrome. The genotype can also be used a posteriori as a stratification factor.

In some diseases, such as HIV infection, patients are expected to be on life-long treatment. Treatment is frequently changed because of toxicity or failure (182), and patients will possibly participate in multiple trials over the years. In this circumstance, certain authors propose the use of a "CYP passport" for volunteers who participate regularly in clinical trials (183). Trials will have to take into account the ethnic origin of the individuals because of its association with genetic polymorphisms (2). However, ethnic denominations may only partially reflect the genetic make-up, and genotyping may reveal more precisely specific associations. A number of X-linked microsatellites and SNP markers are used for the comprehensive analysis of the ethnical structure of the populations (1).

Adequate cohorts and studies have to be developed to allow a very clear definition of a clinical phenotype. This should lead to an integrated database allowing segregation, linkage, and association analysis. Acceptance by participants will be critical in such endeavors. However, in our own experience of offering participation to genetic testing to 1000 HIV-infected patients, the rate of approval has been extremely high at 97%.

These issues (Table 4) are critical, as there is a paucity of in vivo validation of the value of pharmacogenetic markers in predicting treatment response or toxicity of anti-infective agents. Antiretroviral agents are excellent targets for the validation of

Table 4 Validation of Pharmacogenetic Markers in Infectious Diseases

Issues

Comments

Standardized treatment for many diseases

Abundance of clinical trials

Regular participation to consecutive trials

(volunteers, HIV-infected) Use of anti-infective agents in different ethnic groups

Allows coherent collection of data. Phenotype should be carefully defined Allows rapid collection of data. Genotype can be used to better define the target population (smaller and more homogeneous study population) or for stratification for analysis Creation of a "genetic passport"

Ethnic denominations may only partially reflect the genetic make-up. Genotyping could reveal specific associations pharmacogenetic markers in the clinical arena. In one of the first attempts at evaluating known genetic and functional polymorphism of the proteins involved in drug metabolism and disposition, Fellay et al. (20) performed a pilot evaluation in a cohort of well-defined HIV-infected patients receiving protease- or non-nucleoside reverse transcriptase inhibitor-containing regimens. Genetic analysis included the investigation of key polymorphisms of CYP3A4, 3A5, 2D6, 2C19, MDR1, CCR5 (a viral receptor that modifies susceptibility to infection and possibly response to therapy), and also expression of P-gp, MRP1, and MRP2 in lymphocytes. Polymorphisms in MDR1 (C3435T, Exon 26) and CYP2D6 genes were associated with differences in plasma drug levels. MDR1 C3435T was also associated with better immune recovery over the first 6 months of treatment. However, this attempt in evaluating the usefulness of pharmacogenetic markers in vivo generated paradoxical results and considerable controversy. MDR1 3435 TT polymorphism, associated with this and with other studies with a reduction in MDR1 expression (Table 3), was associated with low rather that high drug plasma levels. The association was observed both for the P-gp substrate nelfinavir and surprisingly for efavirenz, which is recognized not to be a substrate of this transporter. The issue is also confounded by a potential role of PIs as inducers or inhibitors of P-gp and by evidence for tissue- and developmental-specific expression of many transporters. Unfortunately, this paradox, possibly explained by the existence of complex compensatory mechanisms (184), underscores the difficulties that will be encountered when applying knowledge obtained from in vitro studies to the clinical field.

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