Educational Forum Antiretroviral drugs: Critical issues and recent advances Mira Desai, Geetha Iyer, R.K. Dikshit ABSTRACT Human immunodeficiency virus (HIV) infection is now recognized as a chronic illness. Although the success of highly active antiretroviral therapy is beyond question, several issues still persist. Since the drugs cannot eradicate the virus, cure is not yet possible, and patients have to maintain a lifelong adherence with the risk of toxic effects, drug-drug Department of Pharmacology, interactions and drug resistance. A clear understanding of the viral replication and its B J Medical College, interaction with host cell factors has led to the development of a large number of effective Ahmedabad, India antiretroviral drugs (ARVs). New drugs in the existing class such as apricitabine, elvucitabine and etravirine have shown promising results against HIV isolates resistant to first line drugs. Received: 01-03-2012 These drugs have offered a new choice for patients with drug resistant disease. However, Revised: 05-03-2012 the impact of their long term use on safety is yet to be assessed. Novel drugs with unique Accepted: 10-03-2012 mechanism of action such as CD4 receptor attachment inhibitors, maturation inhibitors, pharmacokinetic enhancers, capsid assembly inhibitors and lens epithelium derived growth Correspondence to: factor inhibitors are still under development. Currently, ARVs, especially tenofovir and Dr. Mira Desai, emtricitabine, are also being evaluated for prevention of sexual transmission of HIV-1. The E-mail: [email protected] initial results of an HIV prevention trial network are encouraging and have recommended the use of ARVs for pre-exposure prophylaxis. Thus, ARVs form the key component of HIV prevention and treatment strategy. This article discusses the challenges associated with HIV-1 treatment and updates several major advances in the development of ARVs. KEY WORDS: Antiretroviral drugs, challenges, recent advances Introduction continued search for different drug combinations, preferential change in first line drugs and identification of novel drugs A significant advancement in the understanding of an HIV has been a boon for an effective viral suppression. However, replication and its pathogenesis has helped in the identification the success of the drug treatment is achieved at the cost of of different pharmacological targets. This has resulted into life threatening adverse drug effects, drug-drug interactions availability of a large number of antiretroviral (ARV) drugs. The and an inconvenience of lifelong therapy. Since the disease antiretroviral therapy (ART) has evolved from monotherapy has stepped into its 3rd decade, there are several treatment- with azidothymidine (AZT) to combination of 2 ARVs from experienced patients living either with drug toxicity or facing nucleoside reverse transcriptase inhibitors (NRTIs) to highly the threat of treatment failure due to a multi-drug resistance. active antiretroviral therapy (HAART). The triple therapy has Moreover, there is likelihood of newly infected untreated resulted into significant improvement in an immune status, patients harboring HIV mutants that are already resistant to quality of life, and reduced morbidity and mortality associated commonly used ARV drugs.[2] Thus, there are many critical with HIV infection.[1] With the advent of the different drug issues associated with the use of ARV drugs that need to regimens, the disease scenario has changed from a ‘virtual be addressed. In addition, a great deal of attention has also death sentence’ to a ‘chronic manageable disease’. The been focused on prevention of an HIV infection through sexual contact. This article is an attempt to discuss the key issues Access this article online with ARV drugs, review the new agents in existing classes and Quick Response Code: also the novel drugs under development. Website: www.ijp-online.com DOI: 10.4103/0253-7613.96296 Challenges with the Use of ARV Drugs The critical issues associated with ART are related to the characteristic features of the virus (HIV), ARV drugs and HIV positive patients. These factors are a major challenge for an effective long term treatment. 288 Indian Journal of Pharmacology | June 2012 | Vol 44 | Issue 3 Desai, et al.: Advances in antiretroviral drugs HIV related factors The use of over the counter drugs and herbal drugs may 1. HIV, a retrovirus, multiplies at a rate of approximately 1010 potentially compromise the management.[14] copies per day. At such a high rate of replication, the virus 4. Reduction of the plasma viremia to undetectable levels often commits mistakes and results into mutants.[3] High strongly correlates with strict adherence to ARV regimen mutation rate leads to development of multiple strains and that includes taking multiple drugs twice or thrice a day threatens the development of drug resistance. for rest of life. The recommended practice to combine 3 or 2. Once infected, the virus becomes an integral part of host more drugs from different classes of ART results in high pill cell and survives the full life span of infected host cell,[4] count that, along with toxicities, may cause inconvenience especially in T-lymphocytes and urogenital secretions. to the patient and poor adherence.[15] Surprisingly, despite a complete plasma viral load 5. All classes of ARVs demonstrate the in vivo resistance. [2] suppression for 6-12 months, the virus remains detectable However, the rate of development of drug resistance in seminal fluid and more often than not, these are drug differs amongst them. Non-thymidine-containing NRTI/ resistant variants.[5] The existence of virus in potential NtRTI combination regimens and NNRTIs have a low ‘reservoirs’ and the subsequent replication may cause genetic barrier to resistance; thereby, they require fewer relapse following cessation of ART, necessitating lifelong critical mutations to render the treatment ineffective. Drug treatment.[6] Different treatment strategies have been resistance is not only associated with rapid virologic failure tried for the persistent forms, but to date, no clinical or but also present the daunting task in designing an effective virological benefit has been reported.[7] treatment regimen. 3. Increasing reports of multi-drug resistant (MDR) virus 6. The limited availability of ARV drugs and safe alternatives in treatment-experienced patients are also being in resource poor countries further add to the problem. The encountered.[8] lack of monitoring for adverse events and poor access to ARV related factors therapeutic drug monitoring facilities also interfere with 1. Attempts to eradicate the virus from the ‘reservoir’ have effective ART management. failed despite intensifying the ARV treatment, implying that Host related factors drugs cannot reach in adequate concentration in the latent 1. Patients with pre-existing risk factors like obesity, fatty reservoir cells.[7] liver, psychiatric disorders, and abnormal liver and renal 2. Each class of ARV drugs has the potential to cause toxicities, functions are more likely to develop ADRs and require a many of which are shared by drugs likely to be used close monitoring. Presence of co-existing diseases like concomitantly in HIV positive patients. This complicates tuberculosis, anemia, diabetes mellitus and hyperlipidemia the treatment, causes difficulty in causality assessment and further complicate therapy, affect compliance, increase may require treatment withdrawal in serious life threatening chances of drug interactions and overlapping toxicity. reactions. Long term use of HAART has been reported Clinical manifestations of intercurrent illness like hepatitis to produce morphologic and metabolic abnormality A and malaria may often present as ARV drug toxicity and syndrome, especially hypertriglyceridemia (HTG).[9] This challenge the treatment. Hence, it becomes difficult to in turn has increased the risk of cardiovascular (CVS) and differentiate between complications of HIV disease and cerebrovascular diseases in patients receiving ART.[10] ARV toxicity as these may present with similar signs and 3. Clinically significant drug-drug interactions, frequently symptoms. seen in patients on ART, can adversely affect the patient 2. The success of HAART has increased the life expectancy of care and complicate ART. Interactions have been observed HIV patients. This has resulted into increased number of in 14% to 26% of HIV infected patients in USA and patients over 50 years, living with HIV.[16] It is likely that these Netherlands.[11,12] The therapeutic risk of interactions is elderly patients are exposed to broad range of concomitant due to potent induction or inhibition of cytochrome P450 medications along with ARV regimens. However, the choice (CYP450) isoenzyme, which also metabolizes a number of of these medications may not be always straightforward. other medications. On the other hand, the evaluation of The metabolic side effects of these ART increase the risk the potential interactions during clinical trials is mostly of CVS disease.[10] The selection of antihypertensive and incomplete and becomes evident only during drug therapy. antihyperlipidemic agents need extra care, and the most Further, the drugs belonging to same class also differ in appropriate drug may not always be a first line agent. their potential to cause the interactions. For example, first 3. Many ARVs are contraindicated or may require dose licensed integrase inhibitor, raltegravir is predominantly modification or adjustment