Highly Active Antiretroviral Therapy for treatment of HIV/AIDS patients: Current status and future prospects and the Indian scenario ☆

Abstract As the menace of HIV/AIDS continues to rise, effective drug treatments are required to reach the infected masses. HAART provides durable control of virus replication, however, it is not devoid of unwanted side effects, especially in persons undergoing long-term treatment. The current therapy finds its limitations in the emergence of multidrug resistance, transmission of drug-resistant HIV strains, and a life-long treatment. Moreover, to improve patient adherence and to simplify the treatments, effective fixed dose combinations (FDCs) are needed. The picture of HIV/AIDS in India shows that HIV/AIDS is declining through the country and perhaps through proper measures HIV can be eradicated. Thus, finding novel drug targets and new drugs is the need of the hour to treat the infected persons and to reach HIV reservoirs in the body, like brain, lymph nodes, etc. to achieve the ultimate goal, i.e., the complete eradication of the dreaded virus – HIV, the causative agent for AIDS.

[1]  Joel E Gallant,et al.  Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. , 2004, JAMA.

[2]  Luis Menéndez-Arias,et al.  Molecular basis of human immunodeficiency virus drug resistance: an update. , 2010, Antiviral research.

[3]  R. Haubrich,et al.  Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment , 2009, AIDS.

[4]  B. Hirschel,et al.  A new era of antiretroviral drug toxicity , 2008, Antiviral therapy.

[5]  D. Taylor,et al.  In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection , 2006, Antimicrobial Agents and Chemotherapy.

[6]  William M Valenti HAART is cost-effective and improves outcomes. , 2001, The AIDS reader.

[7]  Y. Pommier,et al.  Integrase inhibitors to treat HIV/Aids , 2005, Nature Reviews Drug Discovery.

[8]  J. Chermann,et al.  Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). , 1983, Science.

[9]  L. Osterberg,et al.  Adherence to medication. , 2005, The New England journal of medicine.

[10]  E. De Clercq,et al.  The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2',3'-didehydro-2',3'-dideoxyribonucleosides: a comparison with their parental 2',3'-dideoxyribonucleosides. , 1987, Molecular pharmacology.

[11]  Rudi Pauwels,et al.  New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. , 2004, Current opinion in pharmacology.

[12]  A. Zolopa The evolution of HIV treatment guidelines: current state-of-the-art of ART. , 2010, Antiviral research.

[13]  G. Dutschman,et al.  Antiviral activity of 2′,3′-dideoxy-β-L-5-fluorocytidine (β-L-FddC) and 2′,3′-dideoxy-β-L-cytidine (β-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro , 1994 .

[14]  W. Greene,et al.  Novel targets for HIV therapy. , 2008, Antiviral research.

[15]  K. Morrow,et al.  Development of topical microbicides to prevent the sexual transmission of HIV. , 2010, Antiviral research.

[16]  B. Korber,et al.  A new classification for HIV-1 , 1998, Nature.

[17]  Robert Craigie,et al.  HIV Integrase, a Brief Overview from Chemistry to Therapeutics* , 2001, The Journal of Biological Chemistry.

[18]  N. Graham,et al.  Potential factors affecting adherence with HIV therapy , 1997, AIDS.

[19]  G. Plosker,et al.  Indinavir , 2012, Drugs.

[20]  S. Hughes,et al.  Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (+/-)-calanolide A and its enantiomers. , 1996, Journal of medicinal chemistry.

[21]  E. Rosenberg,et al.  Antiretroviral resistance during successful therapy of HIV type 1 infection. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  K. Bragman,et al.  Saquinavir: an HIV proteinase inhibitor. , 1996, Advances in experimental medicine and biology.

[23]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[24]  M. Gottlieb,et al.  Initial virological and immunologic response to highly active antiretroviral therapy predicts long-term clinical outcome. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  N. Miller,et al.  Compliance with treatment regimens in chronic asymptomatic diseases. , 1997, The American journal of medicine.

[26]  M. Chesney,et al.  Adherence to HIV combination therapy. , 2000, Social science & medicine.

[27]  N. Parkin,et al.  In Vitro Activity of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor (NRTI), against 215 HIV-1 Isolates Resistant to Other NRTIs , 2005, Antiviral chemistry & chemotherapy.

[28]  L. Heise,et al.  Challenges for the development of female-controlled vaginal microbicides. , 1994, AIDS.

[29]  M. Hirsch,et al.  Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1 , 2005, Antimicrobial Agents and Chemotherapy.

[30]  B A Craig,et al.  Estimating AIDS-free survival in a severely immunosuppressed asymptomatic HIV-infected population in the era of antiretroviral triple combination therapy. Swiss HIV Cohort Study. , 1999, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[31]  J. Mellors,et al.  Simplification Strategies to Reduce Antiretroviral drug Exposure: Progress and Prospects , 2009, Antiviral therapy.

[32]  Mark S Roberts,et al.  Long-Term HIV/AIDS Survival Estimation in the Highly Active Antiretroviral Therapy Era , 2003, Medical decision making : an international journal of the Society for Medical Decision Making.

[33]  C. Rouzioux,et al.  Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. , 2009, The Journal of clinical investigation.

[34]  J. Balzarini Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives , 1994, Pharmacy World and Science.

[35]  Praphan Phanuphak,et al.  Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients , 2006, AIDS.

[36]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. , 1998, JAMA.

[37]  J. Adams,et al.  Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. , 1990, Science.

[38]  J. Fox,et al.  Sexual transmission of HIV-1. , 2010, Antiviral research.

[39]  Michael Greenberg,et al.  Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes , 2004, Nature Reviews Drug Discovery.

[40]  A. Carr Toxicity of antiretroviral therapy and implications for drug development , 2003, Nature Reviews Drug Discovery.

[41]  L. Boone,et al.  1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity , 1997, Antimicrobial agents and chemotherapy.

[42]  Erik De Clercq,et al.  Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives , 1990, Nature.

[43]  R. Schinazi,et al.  Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro , 1994, Antimicrobial Agents and Chemotherapy.

[44]  R F Schinazi,et al.  Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine , 1992, Antimicrobial Agents and Chemotherapy.

[45]  B. Gazzard,et al.  Tenofovir Disoproxil Fumarate, Emtricitabine, and Efavirenz Compared With Zidovudine/Lamivudine and Efavirenz in Treatment-Naive Patients: 144-Week Analysis , 2008, Journal of acquired immune deficiency syndromes.

[46]  Vincent Idemyor,et al.  Human Immunodeficiency Virus (HIV) Entry Inhibitors (CCR5 Specific Blockers) in Development: Are They the Next Novel Therapies? , 2005, HIV clinical trials.

[47]  S. Hammer,et al.  Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. , 1997, JAMA.

[48]  Z. Sweeney,et al.  Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: the development pipeline and recent clinical data. , 2008, Current opinion in drug discovery & development.

[49]  K. K. Graham,et al.  Lopinavir‐Ritonavir: A New Protease Inhibitor , 2001, Pharmacotherapy.

[50]  T. Matthews,et al.  A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. , 1993, AIDS research and human retroviruses.

[51]  L. Resnick,et al.  U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication , 1993, Antimicrobial Agents and Chemotherapy.

[52]  David A. Price,et al.  Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity , 2005, Antimicrobial Agents and Chemotherapy.

[53]  J Leibowitch,et al.  Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). , 1983, Science.

[54]  R. Gallo,et al.  Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. , 1984, Science.

[55]  M. Wainberg,et al.  Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2′-Deoxy-3′-Oxa-4′-Thiocytidine , 1999, Antimicrobial Agents and Chemotherapy.

[56]  D. Potvin,et al.  Metabolic effects of a growth hormone-releasing factor in patients with HIV. , 2007, The New England journal of medicine.

[57]  D W Barry,et al.  3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Shibo Jiang,et al.  Design of a protein surface antagonist based on alpha-helix mimicry: inhibition of gp41 assembly and viral fusion. , 2002, Angewandte Chemie.

[59]  M. Baba,et al.  Highly Potent Inhibition of Human Immunodeficiency Virus Type 1 Replication by TAK-220, an Orally Bioavailable Small-Molecule CCR5 Antagonist , 2005, Antimicrobial Agents and Chemotherapy.

[60]  Robert A. Domaoal,et al.  Structural and biochemical effects of human immunodeficiency virus mutants resistant to non-nucleoside reverse transcriptase inhibitors. , 2004, The international journal of biochemistry & cell biology.

[61]  S. Becker,et al.  Fosamprenavir: advancing HIV protease inhibitor treatment options , 2004, Expert Opinion on Pharmacotherapy.

[62]  R. Royce,et al.  Sexual transmission of HIV. , 1997, The New England journal of medicine.

[63]  A. Hill,et al.  Darunavir (TMC114): a new HIV-1 protease inhibitor , 2007, Expert opinion on pharmacotherapy.

[64]  S. Broder,et al.  The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. , 2010, Antiviral research.

[65]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[66]  A. Fauci,et al.  The AIDS epidemic--considerations for the 21st century. , 1999, The New England journal of medicine.

[67]  Lynne Peeples,et al.  Class-sparing regimens for initial treatment of HIV-1 infection. , 2008, The New England journal of medicine.

[68]  A. Cheng,et al.  The Safety and Efficacy of Tenofovir DF in Combination with Lamivudine and Efavirenz Through 6 Years in Antiretroviral-Naïve HIV-1—Infected Patients , 2007, HIV clinical trials.

[69]  R. Schinazi,et al.  L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: asymmetric synthesis and structure-activity relationships. , 1993, Journal of medicinal chemistry.

[70]  Stephen H Hughes,et al.  In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). , 2005, Journal of medicinal chemistry.

[71]  Elizabeth Connick,et al.  Antiretroviral-drug resistance among patients recently infected with HIV. , 2002, The New England journal of medicine.

[72]  K. Gustafson,et al.  The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum. , 1992, Journal of medicinal chemistry.

[73]  J. Balzarini,et al.  Potent DNA chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2',3'-dideoxyuridine-5'-triphosphate. , 1990, Molecular pharmacology.

[74]  E. Clercq New approaches toward anti-HIV chemotherapy. , 2005 .

[75]  Erik De Clercq,et al.  Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and Future , 2004, Chemistry & biodiversity.

[76]  R T Walker,et al.  Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative. , 1989, Biochemical and biophysical research communications.

[77]  D. Hazuda,et al.  Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. , 2008, Journal of medicinal chemistry.