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The Pharmacogenomics of HIV Therapy

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The Pharmacogenomics of HIV Therapy The Pharmacogenomics Journal (2001) 1, 243–253 2001 Nature Publishing Group All rights reserved 1470-269X/01 $15.00 www.nature.com/tpj CLINICAL IMPLICATIONS ¼ patients with primary HIV infection, The pharmacogenomics of HIV ¼ patients with asymptomatic HIV infection and therapy ¼ patients with symptomatic HIV dis- ease or AIDS. M Pirmohamed and DJ Back The recommendations of the British HIV Association (BHIVA; http://www. Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton bhiva.org) are summarised in Table 2. Street, Liverpool, UK The putative benefits of treatment dur- ing primary HIV infection (PHI) have AIDS turned 20 years old on 5 June use of pharmacogenomics has the to be weighed against the known risks 2001; it has to date claimed the lives of potential to resolve some of the prob- of toxicity. Furthermore, despite sup- 21 million individuals, mostly within lems with currently available anti-HIV pression of viral load, HIV replication Africa.1 During the last 20 years, there drugs as well as with the new drugs may continue with an associated risk has been remarkable progress in the being developed. An additional area that of development of drug resistance or therapy of HIV disease. At the beginning, needs to be considered in relation to HIV transmission of drug resistant virus.6 It all that was offered was prophylaxis and therapy is the genetic diversity of the has to be assumed that lifelong treat- treatment of the opportunistic infections virus itself. The purpose of this review is ment will be required even when that are the hallmark of immunodefi- to highlight potential areas where phar- initiated in PHI. All patients with late ciency. The first drug that was active macogenomics may be of use in both disease and/or symptomatic HIV with Ϫ against HIV, zidovudine (AZT), was maximising the efficacy and minimising a CD4 count below 200 cells ␮l 1 or licensed in 1987 in the US. Since then, the toxicity of antiretrovirals, in parti- who have been diagnosed with AIDS advances have not only involved the cular to: or severe/recurrent HIV related illness development of new drugs, but also the should start therapy. The debate of ¼ use of these drugs in appropriate combi- improve the failure rate of current when to start treatment tends to nations. The use of so-called highly drug regimes; centre on patients with established ¼ active antiretroviral therapy (HAART) overcome the problems associated HIV infection but who are asympto- since 1995 has led to a remarkable with kinetic variability of antiretrovir- matic. Ultimately the decision must be improvement in the prognosis of HIV dis- als; and to ensure that the benefits of currently ¼ ease:2 there has been a decrease in AIDS- reduce the short- and long-term tox- available therapies outweigh the risks related deaths, reduction in the use of icities of the drugs. of deferring therapy. drugs for opportunistic infections, and a Evidence is overwhelming that decrease in the numbers of patients hos- CURRENT PRACTICE AND patients should commence therapy 2,7,8 pitalised with AIDS-related illnesses. HIV PROBLEMS OF ANTI-HIV with a HAART regimen. Any can now be classified as a chronic dis- THERAPY HAART regimen should be individual- ease; until a cure is found, patients are The currently licensed antiretrovirals ised in order to achieve the best likely to require life-long therapy. How- fall into three classes, nucleoside potency, adherence and tolerability, to ever, despite these undoubted advances, reverse transcriptase inhibitors minimise toxicity and avoid problems there are many issues that need to be (NRTIs), non-nucleoside reverse tran- of drug–drug interactions. The aim Ͻ resolved, including the problems asso- scriptase inhibitors (NNRTIs) and pro- must be to achieve a viral load 50 Ϫ1 ciated with long-term efficacy and tox- tease inhibitors (PIs)4 (Table 1). With HIV-RNA copies ml at 6–9 months. 4 icity. the available drugs, eradication of HIV The choice of initial therapy is: Pharmacogenomics has been widely is not likely to be possible. The aim of ¼ 2NRTIs ϩ NNRTI hailed as a means to improve prescribing treatment is therefore to prolong life ¼ 2NRTIs ϩ PI for all drugs.3 However, pharma- and improve the quality of life by ¼ 2NRTIs ϩ 2PIs (the primary reason cogenomics is likely to be particularly maintaining suppression of viral repli- for combining PIs is to improve 5 useful for drugs that have variable kin- cation for as long as possible. There is pharmacokinetics. There is wide use etics and dynamics, and a narrow thera- controversy as to the stage of disease of ritonavir as a pharmaco- peutic index. Anti-HIV drugs certainly fit drug therapy should be commenced enhancer). this category. Although there are many and differences may exist in treatment ¼ 3NRTIs. issues that need to be handled in the guidelines. The three groups of treat- next 20 years in the fight against HIV,1 ment naive patients for whom treat- Despite the undoubted short-term individualisation of therapy through the ment guidelines are required are: efficacy of these combinations, it has HIV pharmacogenomics M Pirmohamed and DJ Back 244 Table 1 Currently licensed antiretroviral drugs viduals, and form the basis for either failure or toxicity of the different Nucleoside reverse Non-nucleoside reverse Protease inhibitors (PIs) drug regimes. transcriptase inhibitors transcriptase inhibitors (NRTIs) (NNRTIs) GENOMICS OF VIRAL RESISTANCE Zidovudine (ZDV) Nevirapine (NVP) Saquinavir (SQV) The goal of antiretroviral therapy is to Didanosine (ddI) Efavirenz (EFV) Ritonavir (RTV) completely suppress viral replication. Stavudine (d4T) Delavirdine (DLV)a Indinavir (IDV) Zalcitabine (ddC) Nelfinavir (NFV) If left untreated, HIV replicates at a 13 Lamivudine (3TC) Amprenavir (APV) rapid rate. Taken together with the Abacavir (ABC) Lopinavir & low dose fact that HIV has a high propensity to ritonavir (LPVr) mutate, it is likely that each new virus particle will contain at least one a Not licensed in the UK. mutation.13 During the process of transcription of the proviral DNA from the viral RNA, reverse transcriptase Table 2 Summary of recommendations of when to start treatment (British makes errors relatively frequently. The HIV Association) errors can be of two main types: substi- tutions, where one nucleotide replaces Presentation Surrogate markers Recommendation another and insertions/deletions of one or more nucleoside in the proviral Primary HIV Infection If treatment considered, start as DNA chain. Given the high level of soon as possible, certainly viral replication and turnover within 6 months of con- (typically around 109 viral particles per tracting HIV. day14), this creates the potential for Clinical trial if available. large numbers of genetically distinct Established asymptomatic CD4 Ͼ350 cells ␮lϪ1 Defer treatment. quasi species to be created. Some HIV infection & any viral load mutations result in small changes in CD4 200–350 cells ␮lϪ1 Start treatment taking into the structure of proteins such as account symptoms, rate of reverse transcriptase and/or protease. CD4 decline, viral load and If these changes are at the site of patient wishes action of antiretroviral drugs, then it is CD4 Ͻ200 cells ␮lϪ1 Treat possible that one or more drugs will & any viral load not bind correctly to the target pro- tein. Ongoing viral replication will Symptomatic HIV or AIDS Treat occur in the presence of drug and a resistant quasi species will become the dominant form of the virus in the patient. The clinical implication of this is that once resistance develops, been shown in a meta-analysis that HAART; although many of these the treatment will fail and disease may only 46% of patients were able to adverse effects are minor and depen- progress.15 Some of the key mutations reach the targeted HIV viral load (Ͻ50 dent on dose, they nevertheless affect associated with the development of copies mlϪ1) by 48 weeks.9 Even if the tolerability of HAART, and hence resistance are shown in Table 3. there is initial success, many patients adherence to it.11 Recently, and per- The importance of viral resistance in eventually have to change their initial haps more worrying in respect of the reducing success rates is evidenced by drug regime either because of viral long-term effects of HAART, have been the fact that patients who are treat- rebound or toxicity. For example, in reports of lipodystrophy, a fat redistri- ment-experienced have lower success the Swiss cohort study, rebound HIV bution syndrome associated with rates on second-line and salvage ther- viraemia was approximately 10% per metabolic abnormalities that may apies.16 Genotypic assays that detect year in treatment-naive patients com- have consequences for the develop- mutations have been shown to predict mencing therapy, and 20% per year ment of atherosclerosis in this patient response to antiretrovirals.17–21 For in treatment-experienced patients cohort.12 The levels of the drugs example, among patients who experi- switching therapy.6 In another cohort, within the blood and tissues, how they enced HAART failure, viral suppression viral rebound was observed in 50% of are handled by the body, and the (Ͻ500 copies mlϪ1) at 12 weeks was patients within 12 months of achiev- effect they have on host biological more common among patients for ing undetectable viral RNA.10 Toxicity processes (as opposed to the virus) are whom genotypic anti-retroviral resist- is observed in many patients on all subject to variation between indi- ance testing and clinical
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