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Host Pharmacogenomics: to be Remembered while Planning a Cure for HIV. Vijay Nema1* ... (AIDS)- related deaths, reduction in the use of drugs for opportunistic ... used to identify potential for disease, drug response, and adverse reactions.

BAOJ HIV Vijay Nema and Hari Om Singh, BAOJ Hiv 2017 3: 1 3: 022

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Host Pharmacogenomics: to be Remembered while Planning a Cure for HIV Vijay Nema1* and Hari Om Singh1 Dept. of Molecular Biology, National AIDS Research Institute, Pune 411026, India

Abstract Human Immunodeficiency Virus (HIV) infection has been a global problem and all measures were undertaken to prevent and treat the infection. However, challenges were multifaceted. From Social and behavioral problems to the drug resistance of the virus were all there to challenge our ability to fight with HIV. We have evolved from those days of panic now and drugs seem to be working as evident by the falling rate of new infections and transmissions. The world is thinking about curing HIV and research is ongoing on various fronts. One aspect which needs separate attention and wide studies is host pharmacogenomics. We may get wonder drugs, but to make them work, we also need to know about the host system and if the system is ready to make a right use of the drug and there would be no toxicity. The present review discusses all such aspects to highlight the importance of host pharmacogenomics while considering the cure of HIV infection.

Introduction The success of antiretroviral therapy (ART) in restricting the transmission [1] and raising the life expectancy of the infected individuals [2], have provided the evidence and courage to think about curing Human Immunodeficiency Virus (HIV) infection. The measurable outcomes of using highly active antiretroviral therapy (HAART) have improved the overall scenario as there has been a decrease in Acquired Immunodeficiency Syndrome (AIDS)related deaths, reduction in the use of drugs for opportunistic infections, and a decrease in the numbers of patients hospitalized with AIDS-related illnesses. HIV can now be classified as a chronic disease; until a cure is found, patients are likely to require lifelong therapy. With the evidence till date, it seems that the cure may become a possibility with effective drugs only. Currently used drugs have succeeded partially, in restricting viral multiplications, however, the latent reservoirs serves as a new source of replication and drug resistant virus. Cure research is all about targeting these hidden virus and clearing them using the available antivirals. The strategy seems promising and has proved effective with upcoming evidence [3]. A very recent work discovered a biomarker that is found only on the surface of HIV-infected white blood cells that can be used to eradicate reservoirs of the viral infection throughout the body [4]. A few problems in doing so are the emergence of drug resistance strains of the virus and drug toxicities to the host which may require newer drugs. Hence, an additional but important area that needs to be BAOJ Hiv, an open access journal

considered in relation to HIV therapy is the genetic variability of the host genes which participate in drug metabolism. This concept of pharmacogenomics is imperative with respect to the efficacy of the treatment and handling the toxicity of antiretrovirals. This can aid in tackling the failure of current drug regimens and reducing the short- and long-term toxicities of the drugs. It has been demonstrated by various studies that in a small group of individuals there is a change in nucleotide (polymorphism) in the genes which are responsible for the conversion of antiretroviral drugs into their active forms, their transport and their levels in the blood. This polymorphism of a single nucleotide (SNP), can alter the whole cycle of drug utilization and hence may sometimes result in drug toxicities [5-7]. Hence, it may happen sometimes that the drug is effective on infecting virus but is not reaching the target because of the host genetic constitution. The treatment may fail or may induce various types of toxicities in such cases. The need is to individualize the therapy in order to achieve the best potency, adherence, and tolerability, to minimise toxicity.

Why Genomic Characteristics of Some Individuals becomes a Hurdle in a Cure? The treatment has been a great success in terms of limiting new infections and extending the lifespan of the HIV-1 infected individuals. However, a group of individuals lands into the failure of treatment. This could have clinical, immunologic, virologic reason, or any combination of the three. It means, either their immune system has come to a point wherefrom recovery becomes impossible, or they harbor a virus that is resistant to the current regimen or have issues with adherence. Another big reason that is not accounted for is the genetic makeup of the patient. These individuals may carry a gene which is polymorphic and is *Corresponding author: Vijay Nema, Dept. of Molecular Biology, National AIDS Research Institute, Pune 411026, India, Tel:+91-2027331200; E-mail: [email protected] Sub Date: 10 April, 2017, Acc Date: 19 April, 2017, Pub Date: 20 April, 2017. Citation: Vijay Nema and Hari Om Singh (2017) Host Pharmacogenomics: to be Remembered while Planning a Cure for HIV. BAOJ Hiv 3: 022. Copyright: © 2017 Vijay Nema and Hari Om Singh. This is an openaccess article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Volume 3; Issue 1; 022

Citation: Vijay Nema and Hari Om Singh (2017) Host Pharmacogenomics: to be Remembered while Planning a Cure for HIV. BAOJ Hiv 3: 022.

responsible for failure in drug metabolism or immune function. These factors can basically be classified into two groups- one that involves host genes which interact with the virus at one or the other stage during the viral life cycle and controls the immune response. The other group constitutes genes responsible for drug metabolism. The first group has genes for Chemokine receptor, Chemokine, genes involved in HIV budding, genes responsible for HIV-1 restriction, genes for immune response and cytokines. The second group, directly related to pharmacogenomics, involve the genes responsible for absorption, distribution, metabolism and excretion of the drugs. Mutations/polymorphism in these genes could cause alterations in gene expression or protein structure. This alteration leads to variations in protein quantity and quality. Changes in drug-receptor or drug–enzyme interactions due to structural alterations of enzymes or receptors could also result in variations in drug responses. The responses could be ‘no drug response’ or ‘an increased drug response’ leading to adverse drug reactions or toxicities. Polymorphisms in genes responsible for drug transport can affect pharmacokinetic properties of an administered drug and ultimately its plasma concentration as well as concentrations in the target tissues.

Enzymes and their Polymorphism Inter-individual genetic variations have been associated with and used to identify potential for disease, drug response, and adverse reactions. The application of genetic data for the prediction of response to medications and adverse drug reactions is becoming a reality in some clinical fields. For instance, human leukocyte antigen (HLA)-B*5701allele is being used as a pharmacogenetic marker for abacavir hypersensitivity. Standardizing the test of HLA-B*5701allele for various populations can be useful to help HIV-infected individuals requiring treatment [8]. The capability of a drug regimen to treat an infection mostly depend on how the drug is getting into the system and what course it takes after its entry. In HIV infection, drug molecules which are Nucleoside reverse transcriptase inhibitors (NRTIs), Nucleotide reverse transcriptase inhibitors (NtRTI), Non- Nucleoside reverse transcriptase inhibitors (NNRTI), Protease Inhibitors (PI) etc. are employed in various combinations for the treatment. These drugs are metabolized by specific metabolic pathways and polymorphism in one or the other enzymes of these pathways may lead to a diversification of enzyme activity resulting in a changed course of drug action. Table 1 enlists a few enzymes which participate in these pathways.

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Polymorphism in these enzyme genes has been observed to be associated with abnormal levels or functions of enzymes. Pirmohamed et al. (2000) observed that cytrochrome P450s alleles, i.e. CYP2C9*2/*3 genotype and CYP2C9*3 allele frequencies were nine- and 2.5-fold higher in the hypersensitive group compared to non-sensitive patients in studied population from the UK [9]. In another interesting study, Ramachandran et al., (2009) from Chennai, India have reported that CYP2B6 G516T polymorphism but not rifampin co administration influences steady-state pharmacokinetics of efavirenz in HIV-infected patients in South India. It was TT genotype of CYP2B6 that was associated with exposure to efavirenz in HIV-infected patients in South Indian population [10]. Berno et al. (2014), from Italy have analyzed the potential implications of CYP3A4, CYP3A5 and MDR-1 genetic variants on the efficacy of Lopinavir/Ritonavir (LPV/r) monotherapy in HIV-1 patients and have concluded that CYP3A5 and MDR1-C3435T gene variants may affect the response to Lopinavir/Ritonavir monotherapy [11]. Lu et al. (2014) concluded that the availability of lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be under dosed in people homozygous for the CYP3A5*1 allele, including almost one-half of African Americans [12]. Kwara et al. (2009) have studied NRTI pharmacokinetics in HIV/TB co-infected Ghanaians and attributed UGT2B7*1c polymorphism with relatively high inter individual variability in zidovudine clearance [13]. Utility of Polymorphism Detection Patients treated with abacavir (ABC) may develop a potentially fatal ABC-associated hypersensitivity syndrome (ABC-HS), typically characterized by fever, malaise, rash, vomiting/diarrhoea and/ or dyspnoea/cough. ABC-HS has been strongly associated with HLA-B*57:01 carriage and screening for this allele is recommended [14]. Sequence-based or RFLP-based genotyping and polymerase chain reaction (PCR) sequencing of specific oligonucleotide probes are the most widely used techniques. However, the usage is limited to fewer centres at this point of time and need to be employed in other settings too. As minimizing adverse effects of antiretroviral therapy is critical to controlling the infection and maintaining treatment adherence, probing more and more such polymorphism in different populations becomes very important. Evidence generated with such studies can be directly converted into diagnostic tests which would further aid in reducing adverse reactions.

Table 1: Enzymes which metabolize various drugs used in HIV infection. Drug category

Metabolizing enzymes

Selected references

NRTIs and NtRTI

UGT1A1 and UGT2B7 isozymes

[22,23]

NNRTIs

CYP2B6, UGT2B7, CYP2C19, YP3A4/5, CYP2B6, CYP3A4/5

[24]

Protease inhibitors

CYP3A4/5, CYP2C19

[25,26]

Integrase inhibitor

UGT1A1

[27,28]

CCR5 co-receptor inhibitor (Maraviroc)

CYP3A4/5

[29]

BAOJ Hiv, an open access journal

Volume 3; Issue 1; 022

Citation: Vijay Nema and Hari Om Singh (2017) Host Pharmacogenomics: to be Remembered while Planning a Cure for HIV. BAOJ Hiv 3: 022.

Upcoming Evidences Some of our studies tried to probe a few genes for their polymorphism and their association with adverse events. We reported polymorphism in Glutathione Transferases (GST) wherein, GSTT1-null and STM1-null genotypes alone and in combination may predict the acquisition of hepatotoxicity. The carriers GSTM1-null+GSTT1-null genotype among nevirapine user showed the risk of hepatotoxicity in HIV-infected individuals. Also, the CYP1A1m1 gene may have a role in the development of ARV associated hepatotoxicity and could be helpful in identifying a predictor for the choice of drug (5-7). NNRTIs are predominantly metabolized by CYP450 enzyme system, including 3A4, 2D6, 2B6, 2C9 and 2C19 isoenzymes. Also, they act as inhibitors or inducers of these enzymes, further complicating the potential for significant interactions with other drugs [15,16]. Study of CYP2B6, CYP2C9, CYP2C9, CYP2D6 may provide predictor for nevirapine-induced severe hepatotoxicity. Taking leads from various studies, new drugs are being developed to avoid the reported toxicities and utilizing different pathways. A series of integrase stand transfer inhibitors (InSTIs) has been developed and being used in order to have better efficacy and safety. Some InSTIs like Elvitegravir (EVG), raltegravir (RAL) and dolutegravir (DTG) are recommended as first-line options for treatment-naive patients by the European AIDS Clinical Society, British HIV Association, International AIDS Society-USA and DHHS [17]. RAL and DTG are not metabolized via cytochrome P450 (CYP) which result in fewer drug interactions and less toxicity risk in patients. However, Elvitegravir is predominantly metabolized via cytochrome P450 (CYP)3A4 and study of CYP3A4 polymorphism may provide predictor for Elvitegravir [18]. Ethnicity Issues- Variety of Variations Inter-individual response to drugs in patients greatly varies because genetic background of the population is different. The drugs used in the treatment of individuals have varying clinical implications resulting from genetic polymorphisms in drug metabolizing enzymes (DMEs). Global mixing of Asian, African, European, and Native American ancestries with each other and within their own populations, has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry might introduce genetic variation, which has the potential to alter the therapeutic efficacy of various drugs including the antivirals. Hence large consortium-based sequencing studies are required to provide a diverse genome map of different admixed populations, which can be used for future pharmacogenetic studies. These studies may include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches accounting for ancestral genetic structure, complex haplotypes, gene-gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci. The other issues for developing such studies and linking their outcomes with the predictions of treatment success or failure are the availability of a well-powered sample size,

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information about lifestyles including ethnicity, substance use and other environmental factors. The Contribution of Environmental Factors Environmental factors such tobacco, alcohol and dietary factor play very important role in HIV disease progression. In a recent study from China, among HIV-infected participants, the proportions of those experiencing harmful effects of tobacco and alcohol on AIDS were 53.6% and 72.5%, respectively [19]. Another study showed that heavy alcohol consumption had a negative impact on the CD4 cell count of HIV-infected people not on combined antiretroviral therapy [20]. Along with many other past studies, a recent study from New York City metropolitan area showed that recent tobacco smoking was independently associated with unsuppressed viral load and low CD4 cell count [21]. Not only these, the food habits, use of traditional medicines along with ART etc. may have a positive or negative effect on the metabolism of drugs and hence may influence the expected outcomes of the treatment.

Conclusions With the discussion above, we can say that progress have been made in the area of treatment and hopes are high that one day we would be able to clear the HIV reserves from the human body. With the support of upcoming evidence, we may have better diagnostic modalities available for individuals who become eligible for treatment or when there is a test and treat policy implemented. This would aid in knowing the best fitting regimen for a given individual. However, for those who have polymorphic genes, we need to have the alternate arsenal available. This further necessitates intensive research in new drug discovery with better efficacy and minimal side effects to complete our preparation for HIV-cure.

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Citation: Vijay Nema and Hari Om Singh (2017) Host Pharmacogenomics: to be Remembered while Planning a Cure for HIV. BAOJ Hiv 3: 022.

7. Singh HO, Lata S, Angadi M, Bapat S, Pawar J, et al. (2017) Impact of GSTM1, GSTT1 and GSTP1 gene polymorphism and risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation. Pharmacogenomics J 17(1): 53-60. 8. Ventola CL (2011) Pharmacogenomics in clinical practice: reality and expectations. P T 36(7): 412-450. 9. Pirmohamed M, Alfirevic A, Vilar J, Stalford A, Wilkins EG, et al. (2000) Association analysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity. Pharmacogenetics 10(8): 705-713. 10. Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Kumar P, Ramesh K, et al. (2009) CYP2B6 G516T polymorphism but not rifampin coadministration influences steady-state pharmacokinetics of efavirenz in human immunodeficiency virus-infected patients in South India. Antimicrob Agents Chemother 53(3): 863-868. 11. Berno G, Zaccarelli M, Gori C, Tempestilli M, Pucci L, et al. (2014) Potential implications of CYP3A4, CYP3A5 and MDR-1 genetic variants on the efficacy of Lopinavir/Ritonavir (LPV/r) monotherapy in HIV-1 patients. J Int AIDS Soc 17(4 Suppl 3): 19589. 12. Lu Y, Fuchs EJ, Hendrix CW, Bumpus NN (2014) CYP3A5 genotype impacts maraviroc concentrations in healthy volunteers. Drug Metab Dispos 42(11): 1796-802. 13. Kwara A, Lartey M, Boamah I, Rezk NL, Oliver-Commey J, et al. (2009) Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation. J Clin Pharmacol 49(9): 1079-1090. 14. Carolino F, Santos N, Piñeiro C, Santos A S, Soares P, et al. (2017) Prevalence of abacavir-associated hypersensitivity syndrome and HLA-B*5701 allele in a Portuguese HIV-positive population. Porto Biomedical Journal 2(2): 59–62.

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21. Hile SJ, Feldman MB, Alexy ER, Irvine MK (2016) Recent Tobacco Smoking is Associated with Poor HIV Medical Outcomes Among HIVInfected Individuals in New York. AIDS Behav 20(8): 1722-1729. 22. Ribaudo HJ, Daar ES, Tierney C, Morse GD, Mollan K, et al. (2013) Impact of UGT1A1 Gilbert variant on discontinuation of ritonavirboosted atazanavir in AIDS Clinical Trials Group Study A5202. J Infect Dis 207(3): 420-425. 23. Čolić A, Alessandrini M, Pepper MS (2015) Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine. Drug Metab Rev 47(2): 111-123. 24. Usach I, Melis V, Peris JE (2013) Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability. J Int AIDS Soc 16: 1-14. 25. Mpeta B, Kampira E, Castel S, Mpye KL, Soko ND, et al. (2016) Differences in genetic variants in lopinavir disposition among HIV-infected Bantu Africans. Pharmacogenomics 17(7): 679-690. 26. Green B, Crauwels H, Kakuda TN, Vanveggel S, Brochot A (2016) Evaluation of Concomitant Antiretrovirals and CYP2C9/CYP2C19 Polymorphisms on the Pharmacokinetics of Etravirine. Clin Pharmacokinet 56(5): 525-536. 27. Lee LS, Seng KY, Wang LZ, Yong WP, Hee KH, et al. (2016) Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI. PLoS One 11(1): e0147681. 28. Yagura H, Watanabe D, Ashida M, Kushida H, Hirota K, et al. (2015) Correlation between UGT1A1 polymorphisms and raltegravir plasma trough concentrations in Japanese HIV-1-infected patients. J Infect Chemother 21(10): 713-717. 29. Vourvahis M, McFadyen L, Heera J, Clark A (2015) Clinical relevance of CYP3A5 genotype on maraviroc exposures. Drug Metab Dispos 43(5): 771-772.

15. Ma Q, Okusanya OO, Smith PF, Dicenzo R, Slish JC, et al. (2005) Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors. Expert Opin Drug Metab Toxicol 1(3): 473-485. 16. Smith PF, DiCenzo R, Morse GD (2001) Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 40(12): 893-905. 17. Elliot E, Chirwa M, Boffito M (2017) How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use. Curr Opin Infect Dis 30(1): 58-73. 18. Klibanov OM (2009) Elvitegravir, an oral HIV integrase inhibitor, for the potential treatment of HIV infection. Curr Opin Investig Drugs 10(2): 190-200. 19. Duan S, Jin Z, Liu X, Yang Y, Ye R, et al. (2017) Tobacco and alcohol use among drug users receiving methadone maintenance treatment: a cross-sectional study in a rural prefecture of Yunnan Province, Southwest China. BMJ Open 7(3): e014643. 20. Samet JH, Cheng DM, Libman H, Nunes DP, Alperen JK, et al. (2007) Alcohol consumption and HIV disease progression. J Acquir Immune Defic Syndr 46(2): 194–199.

BAOJ Hiv, an open access journal

Volume 3; Issue 1; 022