Review articles

By Mr. Sushanta K Barik , Dr. Keshar Mohanty , Dr. Srikanth Tripathy , Dr. Umesh Gupta , Dr. Deepa Bisht , Dr. Srikanta Jena , Dr. Partha Mohanty
Corresponding Author Dr. Keshar Mohanty
National JALMA Institute for Leprosy and Other Mycbacterial Diseases, TajganJ - India 282001
Submitting Author Mr. Sushanta K Barik
Other Authors Mr. Sushanta K Barik
National JALMA Institute for Leprosy and Other Mycbacterial Diseases, TajganJ - India 282001

Dr. Srikanth Tripathy
National Institute for Research in Tuberculosis, Chennai - India 600031

Dr. Umesh Gupta
National JALMA Institute for Leprosy and Other Mycbacterial Diseases, TajganJ, Agra - India 282001

Dr. Deepa Bisht
National JALMA Institute for Leprosy and Other Mycbacterial Diseases, TajganJ,Agra - India 282001

Dr. Srikanta Jena
Ravenshaw University, Cuttack,Odisha - India 753003

Dr. Partha Mohanty
National JALMA Institute for Leprosy and Other Mycbacterial Diseases, Tajg-Ganj, Agra - India 282001


HIV: Human-Immuno Deficiency Virus, AIDS: Acquired Immuno-Deficiency Syndrome, NRTIs: Nucleoside Reverse Transcriptase Inhibitors, NNRTIs: Non-nucleoside Reverse Transcriptase Inhibitors, RT: Reverse Transcriptase gene

Barik SK, Mohanty K, Tripathy S, Gupta U, Bisht D, Jena S, et al. Human Immuno-Deficiency Virus Drug Resistance, Nuclesoide Reverse Transcriptase Inhibitors, Non-nuclesoide Reverse Transcriptase Inhibitors and associated drug resistance mutations in the Reverse Transcriptase Gene of Human Immuno Deficiency Virus-1.. WebmedCentral AIDS 2016;7(9):WMC005177

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submitted on: 02 Sep 2016 08:41:04 AM GMT
Published on: 06 Sep 2016 01:19:22 PM GMT


Resistance develops due to mutations in the reverse transcriptase gene of HIV-1 genome that does not respond towards the presence of effective drugs. Emergence of HIV-1 variants in the presence of effective drugs is a common occurrence. Drug resistance mutation means “the development of resistance mutations in the drug targeted HIV-1 genes” which causes the viruses to overcome the drug pressure. Thus resulting in failure to antiretroviral therapy. The detection of these mutations is possible by genotypic assay and the analysis of the effect of different drug concentrations towards the reverse transcriptase gene is possible by phenotypic assay. Genotyping of these mutations gives the information on therapeutic decision at the population and individual level. The frequency of mutation in the HIV-1 genes varies in the same population of a region or a city. The frequencies of mutations in the reverse transcriptase genes of HIV-1 lead to subtype diversity, drug resistance mutations and formation of recombinant  isolates. The frequency of mutations in the reverse transcriptase gene is a cause of treatment failure by nucleoside/ nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors in a population level. The frequency of mutations in the reverse transcriptase gene is directly related to the prevalence of HIV-1 drug resistance mutations in a population or individual level.

This review mainly focuses on the human immunodeficiency virus drug resistance, nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and associated drug resistance mutations in the reverse transcriptase gene of human immuno-deficiency virus-1.

HIV: Human Immunodeficiency Virus, AIDS:Aquired Immunodeficiency Syndrome. HIVDR: Human Immuno deficiency virus drug resistance, NRTIs:Nucleoside reverse transcriptase inhibitors, NNRTIs:Non-nucleoside reverse transcriptase inhibitors, RT: Reverse transcriptase, PIs:Protease inhibitors, TAMs: Thymidine analogous mutations, NonTAMs: Non-thymidine analogous mutations.


Acquired Immuno-Deficiency Syndrome in human beings is caused by two viruses Human Immunodeficiency Virus -1(HIV-1) and Human Immunodeficiency Virus-2 (HIV-2) in which the HIV-1 is more virulent than HIV-2.This disease was first reported in some patients of USA in the year 1981 [1] . HIV-1 groups were classified as group M, group O, group P and a new group N (Non M/Non O). HIV-1 group M pandemic spread in Kinshasa around early 1920s and the epidemic histories of HIV-1 group M and group O were similar until 1960s, after which group M under gone epidemiological transition through social changes and transport networks and established in human population[ 2]. The Global burden of HIV/AIDS is directly related with the disability adjusted life years of the individuals [ 3]. The HIV RNA is ≥ 9 kb, a single stranded RNA consisting of 15 proteins [4]. Human Immuno-Deficiency Virus (HIV) is transmitted by sexual contact, blood transfusion, blood semen, vaginal secretion and breast milk as well as oral sex. During the pregnancy, the HIV is transmitted from mother to the baby or breast feeding. HIV is not transmitted through saliva and casual contact such as kissing or sharing glasses. The first infection of HIV is called primary infection like severe flu, headache, fever, throat, rash, swollen glands, headache, ulcers in mouth [5].It is universally accepted that the highly active antiretroviral therapy (HAART) has reduced the HIV related mortality worldwide. The implementation of ART programmes reduces the morbidity and mortality in the population level. The scaling up of the ART may be controlled the drug resistance mutations and transmission of HIV drug resistance strains in a given population. The combination of antiretroviral therapy regimens were developed in the late 1990s. This therapy is used to suppress the viral replication and decrease the disease progressiveness. India is a developing nation where it required the rapid scale up antiretroviral therapy to decline the mortality and morbidity in the population level [6]  . 

The six drug classes are 1.Nucleoside reverse transcriptase inhibitors 2.Non-nucleoside reverse transcriptase inhibitors 3.Integrase inhibitors 4.Protease inhibitors 5.Fusion inhibitors 6.Coreceptor antagonists. Now a days in many hospitals, the most significant management in HIV infection has been treated by the antiviral drugs. The antiviral drugs suppress the viral replication up to undetectable levels. Now Food and Drug Administration, USA approved twenty five drugs under this six classes drug categories which are available for treatment of HIV-1 infection [7].

Now a days, the most significant way of management in HIV infection is the treatment with antiviral drugs in majority of health settings. At present, the first line treatment for HIV consists of two nucleoside reverse transcriptase inhibitors (NRTI's), a thymidine analog zidovudine , stavudine or lamivudine  and one non-nucleoside reverse transcriptase inhibitor (NNRTI), a cytidine analog nevirapine or efavirenz. The protease inhibitors (PIs) are available for second line treatment options upon failure of first line treatment under national programme. The drug resistance in HIV is defined as "Identification of any drug resistance mutation in human immunodeficiency virus in patients during the combined antiretroviral therapy. The drug resistance mutation recorded the virologic failure of the patients and the date of virologic failure as per the 2010 WHO guidelines on antiretroviral therapy in adults and adolescents defined as the first recorded date of the plasma viral load of more than 5000 copies /ML after six months of treatment. According to WHO protocol CD4 + cells should be < 350 cells / µl in decreasing order followed by HAART is consider as HIV drug resistance [ 8].

The genetic diversity of HIV-1 is extensive by comparing the data from Los Alamos HIV Sequence Data base, HIV db drug resistance interpretation algorithm (version 4.1.9), ANRS drug resistance interpretation algorithm (version 2005.07) and Rega institute drug resistance interpretation algorithm (version 6.4.1), IAS-USA available as online tool[ 9].

HIV Drug Resistance (HIVDR)

The ability of HIV to mutate and reproduce in the presence of antiretroviral drugs is called HIV drug resistance. The viral replicates and survives in the presence of inhibitors like nucleoside/nucleotide inhibitors, non-nucleoside inhibitors, protease inhibitors etc.

Based on the population level HIVDR is divided in to three types 1.Transmitted HIVDR 2 .Acquired HIVDR 3. Pre-treatment HIVDR

1. Transmitted HIV Drugresistance:

Transmission of the drug resistant variants in to newly infected individuals is termed as transmitted drug resistance. The transmitted drug resistance is directly related to ART service, duration as well as fitness of the drug resistance strains that evolve. Transmitted HIVDR is observed in some populations those are unexposed to antiretroviral therapy. After initial infection, the certain drug resistance mutations rapidly changes in to wildtype  due to without drug selective pressure. In some cases exposure of antiretroviral therapy leads to revert the mutations leading to virologic failure. Transmitted HIVDR strains are transferred from one patient to another. The prevalence and incidence rate of HIV-1 was high in the fishing communities on the Lake Victoria in Uganda .Among the population the spread of HIV-1 epidemic is due to transmitted drug resistance (TDR). The TDR data were collected from the Uganda population among the antiretroviral naive and some recently infected individuals about five years after antiretroviral scaling- up. The NNRTIs drug resistance mutation K103N was identified in two individuals and V106A in one individual in naive population of Uganda. It was suggested that the level of TDR was moderate in this population of Uganda. No NRTIs or PIs drug resistance mutations were detected in Uganda population [10].

The HIV prevalence is rising among the men sex with men (MSM) group of population in china. The MSM group were married due to social pressure and therefore, they may have the wives and sexual partners. So the group with transmitted drug resistance have a risk of transmitting the HIV subtypes to both their male and female sexual partners [11].The transmitted drug resistance is an important contribution of local transmission clusters and the spread of resistant virus in the MSM group of Croatia [12].The presence of transmitted drug resistance in treatment naive HIV-1 infected patients gradually increases in the countries like Soviet union where the antiretroviral therapy is exposed [13].

2. Acquired HIVDrugresistance:

This kind of HIVDR emerges in response to drug selective pressure by different drug classes. In case of HIVDR the optimal regimens are provided as well as adherence is supported. This kind of drug resistance mutation develops due to infection with a second strain called as "super infection". A case was reported in HIV-1 super infection with a subtype- B, successfully controlling in viremia with continuous combination of triple class antiretroviral therapy started 8 years earlier during primary HIV infection [14].

3. Pre-treatment HIVDrugresistance:

Pre-treatment HIVDR is emerged in populations initiating antiretroviral therapy for the first time. The pre-treatment HIVDR emerge due to antiretroviral drug exposure during the earliest infection time, the prevention of mother to child transmission, pre exposure prophylaxis, post-exposure prophylaxis. Sometimes poor adherence to ART in a population leads to the drug resistance mutation. A study was reported in Northwest Spain in  the high prevalence subtype F , the non-B subtype among newly diagnosed HIV-1 infected persons.The impaired treatment response to ART leads to slower virologic response in Men Sex with Men (MSM) group of population in Northwest Spain [15]. The prevention of mother to child transmission of HIV is essential by use of suitable regimens. In a population study in five centres of Johannesberg, the treatment naive infected children's were developed drug resistance mutations towards non-nucleoside reverse transcriptase inhibitors.The Y181C confers high level resistance to nevirapine exposed childrens but was confers intermediate  level resistance to efavirenz and etravirine. Although the use of efavirenz in children under three years of age is controversial but the use of lopinavir/ritonavir regimen towards newly diagnosed HIV infected childrens in the era of more efficacious antiretroviral prophylaxis [ 16].

HIV-1 reverse transcriptase

The reverse transcriptase enzyme is responsible for RNA dependent DNA polymerization as well as DNA dependent DNA polymerization. Reverse transcriptase is a heterodimer consisting of two subunits like p66 and p51. The p66 subunit is composed of 560 amino acids and p51 subunit is composed of 450 amino acids. The p66 subunit is active contains the DNA binding groove and active site ,the p51 subunit has no enzymatic activity .The p66 subunits has five domains like fingers, palm, thumb sub- domains which participate in polymerization and the other domains connection and RNase H sub-domains .The nucleoside reverse transcriptase inhibitors are triphosphorylated by the action of host cellular enzymes. The triphosphorylated nucleoside triposphates incorporated in to the newly synthesiz deoxyribonucleotides   to cause chain termination [17].

 Nucleotide/Nucleoside reverse transcriptase inhibitors (NRTIs):

Nucleoside reverse transcriptase inhibitors are the main drug used to treatment of both naive and experienced HIV-1 infected individuals. NRTIs can be divided in to two broad categories like Thymidine analogues mutations (TAMs) and Non-thymidine analogous mutations (Non-TAMs).

The examples of the TAMS are zidovudine  (3'Azido  2'3' di-deoxy guanosine)  and Stavudine  (2'3'-didehydro 3'deoxythymidine). The examples of  Non TAMs are didanosine (2'3'dideoxyinosine),zalcitabine(2'3'dideoxycitidine),lamivudine(2'deoxy3'thiothiadine),emtricitabin e(-)B-1-3'-thio-2'-3'-dideoxy-5flurocytidine,FTC,abacavir(IS,4R)-4-[2-amino-6 (cyclopropylamino)-9H-purin-9-y1]-2cyclo-pentene-1-methanolsuccinate),(ABC) [18].              &nb sp;                & nbsp;                 ;                            & nbsp;                 ;                &nb sp;           



General features of nucleoside reverse transcriptase inhibitors (NRTIs)

General features of thymidine analogus mutation drugs (TAMs):


Zidovudine was the first drug synthesized by Horwitz at the cancer Michigan foundation in the year 1964. This drug has the retroviral activity. In the year 1986, the drug has provided the strong evidence that zidovudine prolongs survival, decrease the severity of infections and improve the quality of life those are infected with HIV/AIDS [19] .Then in the year 1987, zidovudine was first approved drug by food and drug administration. Zidovudine inhibits the activity of reverse transcriptase of HIV-1 but not the activity of human DNA polymerase. The minimum dosage of therapeutic requirement for HIV-1 treatment is 300mg/ twice a day.  Zidovudine has several risks in the body of human being causes bone marrow suppression, headache, fatigue, neutropenia, nausea, vomiting, hematological toxicity, myalgia, anaemia, neutropenia, myopathy and lactic acidosis with hepatosteatosis  is a rare but life threatening mitochondrial toxicity [20].


Stavudine (2'3'-didehydro 3'deoxythymidine) was synthesized by Jerome Horwitz  in the year 1960. It was an HIV agent declared by Rega Institute for Medical Research in Belgium [21]. It was then approved by USA food and drug administration in the 24th June 1994. Stavudine inhibits the activity of reverse transcriptase of HIV-1 but not inhibit the activity of  DNA polymerase. Because of its irreversible side effects, less toxic.Stavudine is used as a first line therapy in developing countries. Stavudine is not metabolized by cytochrome P450. The stavudine is mainly used in opportunistic infections in the human immuno-deficiency virus infected patients [22]. The minimum 30 mg to 40 mg therapeutic dosages required for HIV infected patients. The stavudine induced the multiple adverse effects in HIV infected patients like hepatic steatosis, hyper lactatemia, lipodystrophy, peripheral neuropathy, dyslipidemia, hyperglycemia and mitochondrial dysfunction [23].

General features of the non thymidine analogous mutation (Non TAMs) drugs:


The drug didanosine was initially synthesized by Morris J.Robins and R.K. Robins in the year 1964 [24]. Didanosine became the second USA approved drug by FDA in the year 9th October 1991.The most common effect of  didanosine are diarrhea, nausea, vomiting, abdominal pain, fever, headache and rash [25]. Didanosine is a nucleoside analogue of (2'3' dideoxyinosine) guanosine. It inhibits reverse transcriptase by competing with natural dATP but donot inhibit the activity of DNA polymerase. From the pharmacokinetic study, it is known that, the didanosine is an acid labile anti retroviral agent. The minimum therapeutic dosage is 375mg/day required for treatment of HIV infected patients [26].


Zalcitabine (2′-3′-dideoxycytidine, ddC) was synthesized by Jerome Horwitz and subsequently declared as an anti HIV agent by Samuel Broder, Hiroaki Mitsuya and Robert Yarchoan at the National Cancer Institute [27]. Zalcitabine was approved by Food and Drug Administration on 19th June 1992. Zalcitabine significantly inhibits the intracellular phosphorylation, then convert in to active form. So the drugs are not administered together. Zalcitabine phosphrylated in T cells and other HIV target cells in to active triphosphate forms.This active triphosphate work as a substrate for HIV reverse transcriptase and also incorporating in to the viral DNA. Hence, terminating the chain elongation.The most common adverse effects on human being is nausea, headache, peripheral neuropathy, oral ulcers, peripheral ulcers etc [28].


Lamivuidne (2′, 3′-dideoxy-3′-thiacytidine) was invented by Dr Bernard Belleau in the Mc Gill University and Dr Paul N guyen-Ba at the Monetral based IAF Biochem International incorporation laboratories in the year 1988 and 1989.Dr Yung-Chi Cheng of Yale University reported that lamivudine work well when combine with zidovudine to inhibit the activity of reverse transcriptase .The 300 mg/day is the minimum dose used by the HIV infected patients with zidovudine. Lamivudine has no carcinogenicity or mutagenicity but as less toxic to mitochondrial DNA adverse effects like skin rash has been reported in HIV infected patients those are taking antiretroviral therapy [29, 30].


Emtricitabine is discovered by Dr Dennis C.Liotta, Dr Raymond F. Schinazi and Dr Woo -Baeg Choi, Emory University and immediately licensed by Triangle pharmaceuticals in the year 1996. It was approved by FDA in the 2nd July 2003. Emtricitabine is an analogue of cytidine. Emtricitabine acting well by inhibiting the activity of reverse transcriptase .HIV lower the amount of viral load in the patient body that can increase the number of CD4 cells in the immune system. The treatment of toxicity with Emtricitabine is unusual .The treatment related adverse effects are diarrhea, nausea, vomiting and rash. The severe side effects may experience hepatotoxicity or lactic acidosis. The minimum 600mg/day in combination therapeutic doses required for treatment of HIV infected patients [ 31].


Abacavir is an anti-retroviral drug inhibit the reverse transcriptase used to treat HIV .The main side effect of the drug is hypersensitivity which can be severe. The other side effects are vomiting, diarrhea, nausea etc. Abacavir was approved by FDA on December 18 in the year 1998.The minimum 600mg/day therapeutic doses is required to treat HIV infected patients [32].

Mechanism of chain termination by the nucleoside reverse transcriptase inhibitors (NRTIs) :

Nucleoside reverse transcriptase inhibitors were the first drugs to approve by Food and Drug Administration, USA. Before antiviral effects, the nucleoside reverse transcriptase inhibitors entry in to cells, the phosphorylation occurs by cellular kinases. The absence of 3' hydroxyl group at the sugar moiety of the nucleoside reverse transcriptase inhibitors  prevents the formation of phosphodiester bonds at the 3'-5' end that prevents the bond formation between incoming nucleoside triphosphates (5'end) and nucleoside reverse transcriptase inhibitors. This chain termination event occurs in RNA dependent DNA synthesis or DNA dependent DNA synthesis during the production of proviral deoxyribonucleotides [33].

Mechanism of emergence of drug resistance:

Nucleoside reverse transcriptase inhibitors mutations are occurred in reverse transcriptase and classified as Nucleoside associated mutations or Thymidine analogous mutations. Genetic variations are observed in HIV-1 due to drug selective pressure among the treated and untreated patients those are taking antiretroviral therapy. The emergence of drug resistance mutations is the cause of drug susceptibility towards the HIV strains.

Two types of mechanism are behind for the resistance to nucleoside reverse transcriptase inhibitors. 1. ATP dependent pyrophosphorylysis 2.Prevention of NRTIs in to nascent chain.

1. ATP dependent pyrophosphorylysis: Removal of NRTIs from the 3´end of the nascent chain and chain termination in a reversal way as well as the increased the discrimination between the dNTPs and inhibitors.Thymidine analogous mutations (TAMs) promotes pyrophosphorolysis and involved in the excision of zidovudine (AZT) and stavudine (d4T) [34,35] . Thymidine analogous mutation amino acid changes (TAMs) in HIV-1 reverse transcriptase includes two phases TAM1 and TAM2 phases. The TAM1 pathway amino acid changes includes ( T215Y, L210W, D67N M41L ) and the TAM 2 pathways amino acid changes includes ( D67N, K70R, T215F and 219E/Q) [36,37,38,39,40  ].

2. Prevention of NRTIs in to nascent chain: Some mutations emerge in the reverse transcriptase region which prevent the interaction with nucleoside reverse transcriptase inhibitors. The mutations M 184V, K65R emerge as a resistant in the reverse transcriptase region those patients are taking zidovudine, lamivudine, emtricitabine, abcavir. This mutation decreases the reverse transcriptase  function and replicative fitness of the virus[ 41,42].

 Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

Four non-nucleoside reverse transcriptase inhibitors are presently used by HIV infected patients. The nevirapine, efavirenz, etravirine, rilipivirne are commonly used by HIV infected patients in ART clinic. Based on the resistance activity, two generations of NNRTIs were developed. In first generation NNRTIs nevirapine (NVP), delavirdine (DLV) and efavirenz are drugs with low genetic barrier and poor resistance profile which has led to development of second generation NNRTIs. Etravirine (ETR) and rilpivirine has been developed by Food and Drug Administration as well as European union.

The next generations of NNRTIs is being clinically developed : Lersivirin , MK-1439, MK-6186 GSK 2248761, RDEA806, BILR 355 BS, Calanolide A, MK-4965 and their pharmacokinetics, metabolism, clinical data, safety and tolerability is now on the way of  testing and research [43].

General features of first generation Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

The first NNRTIs to be discovered are 1-(2-2-hydroxyethoxymethyl)-6-(phenylthio) thymine (HEPT) and tetra hydroimidazo [4,5,1-jkj] [1,4] benzodiazepin-2(1H)-one and-thione (TIBO) are specific for HIV-1 inhibitors. Both HEPT and TIBO are highly active compounds against HIV-1 but they are inactive against HIV-2. After HEPT and TIBO, several other compounds were discovered and later on FDA approved as NNRTIs including dipyridodiaze pinones (NVP),bis(heteroaryl)  piperazines (DLV) and benzoxazinones(EFV) [44].

Nevirapine :

Nevirapine  is a dipyridodiazepinone (11-cyclopropyl- 5, 11-dihydro- 4-methyl-6H-dipyrido [3, 2-b: 2', 3'-e] [1,4] diazepin- 6- ranges from 200 mg once daily up to 14 days followed by 200 mg twice daily. In humans, nevirapine undergoes hepatic biotransformation to several hydroxylated metabolites (2-, 3-, 8- and 12- hydroxyl nevirapine) by CYP which is also  an  auto-inducer of isoenzymes 3A4 (CYP3A4) and 2B6 (CYP2B6). Nevirapine is a noncompetitive one). Nevirapine is a low water soluble and lipophilic drug. Beacuse of its weak basic character and ionization, nevirapine exhibits pH dependent solubility .Nevirapine is highly soluble in buffer. The nevirapine is a class-II compound because of its low solubility and high intestinal permeability [45].  Effective dosage inhibitor of HIV-1 reverse transcriptase but does not have a significant inhibitory effect on HIV-2 RT or eukaryotic DNA polymerase α, β, γ, δ. Nevirapine has been given to the pregnant women .The main role of nevirapine is to prevent mother to child transmission of HIV-1 infection [46,47].


 Efavirenz (EFV) is a benzoxazinone derivative (S)-6-chloro-4 (cyclopropylethynyl) -1,4-dihydro-4-(tri-fluoromethyl)-2H-3,1-benzoxazin- 2-one). EFV is a crystalline non-hygroscopic lipophilic materials, class-II drug has the characteristics properties of low solubility and high permeability. In vitro studies demonstrated that Efavirenz is metabolized in the liver by the CYP3A4 and CYP2B6 isoenzymes[ 48]. Effective doses of 200-400 mg daily required for 10 days for the HIV infected patients. Efavirenz is a non-competitive inhibitor of HIV-1 RT but does not have a significant inhibitory effect on HIV-2 reverse transcriptase or on human DNA polymerase α β γ or δ. The mechanism of viral resistance or reduced susceptibility depends upon the mutations of HIV-1 reverse transcriptase [49].


Delavirdine (DLV) belongs to a bisheteroarylpiperazines derivative (N-[2-({4- [3-(propan-2-yl amino) pyridin-2-yl] piperazin-1-yl} carbonyl)-1H-indol-5-yl] methanesulfonamide).Delavirdine is a weak base and no data is available about BCS Class compounds. The DLV therapeutic dose is 400 mg three times a day.The drug is highly protein bound in humans is metabolized  by CYP3A4 into biologically inactive metabolites: N-dealkylated metabolite and unidentified pyridine hydroxy metabolites: N-dealkylated metabolite and unidentified pyridine hydroxy metabolites (including Met-7 and Met-7a [50]. Delavirdine is highly selective for HIV-1 reverse transcriptase and it has minimal effects against HIV-2 reverse transcriptase as well as  human cellular DNA polymerase α and β .Delavirdine has been assigned to the pregnancy  category C by FDA and have no effectiveness has been reported related to age or sex[ 51] .

Second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs):

The second generations NNRTIs include etravirine and rilpivirine which belongs to the family of di-aryl-pyrimidine compounds. This kind of NNRTIs shown better resistance  profile.


Etravirine has been better used in treatment experienced multidrug resistant HIV-1 infected adults where as rilpivirine has been used to treat naïve -treatment HIV-1 infected patients [52].The etravirine a lipophilic  drug has  low solubility, permeability  properties  and categorized under IV class compounds [53].The therapeutic dosages of etravirine is 200 mg twice daily.The etravirine is primarily metabolized by several CYP isozymes like CYP3A, CYP2C9 and CYP2C19[ 54].


Rilpivirin is a (4-[[4-[4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino]pyrimidin-2-yl] amino] benzonitrile) compound  and very poor water soluble compound. Rilpivirine is a class -II compounds with the properties of low solubility and high permeability. Rilpivirine is mainly metabolized by the CYP3A isoenzyme system. Rilpivirine activity is mediated by non competitive inhibition of HIV-1 RT and does not inhibit cellular DNA polymerases like δ, β, γ. The 25 mg of therapeutic dosages of rilpivirine is daily required by the HIV-1 infected patients [55].

Mechanism of   action of   non-nucleoside reverse transcriptase inhibitors:

Non-nucleoside reverse transcriptase is non-competitive inhibitors binding to a hydrophobic pocket in the HIV-1 RT near polymerase active site to stop the polymerization. NNRTIs do not interfere with substrate binding but interfere with the dNTPs binding.                               &nbs p;                &n bsp;       

Drug resistance mutations in HIV-1 reverse transcriptase gene:

The highly active antiretroviral therapy (HAART) includes the two nucleotide /nucleoside reverse transcriptase inhibitors (NRTIs) with one non-nucleoside reverse transcriptase inhibitors (NNRTIs) or one protease inhibitor (PI) or one integrase inhibitor (II). The highly active antiretroviral therapy includes a single tablet regimen used by HIV patients. Resistance mutations development in the reverse transcriptase gene is a cause of treatment failure by the highly active antiretroviral therapy. A single tablet regimen is always associated with viral suppression and higher adherence than multiple tablet regimens in homeless and household AIDS patients [56]. Many times a single tablet regimen is not effective against drug resistance patients. Then they have to change the different combination regimens to treat drug resistance patients. A single tablet regimen tenfovir, emtricitabine and efavirenz is not effective towards the treatment due to the persistence of K65R, K103N and M184V/I reverse transcriptase mutations in HIV-1 infected patients leads to virological  failure[ 57].

Nevirapine which is a highly lipophilic drug shown drug susceptibility in cell culture. Genotypic analysis in the RT region has shown the mutations in the Y181C or V106A depending on the virus strain and type of cell lines. The most common Y 181 C resistance-associated mutations have been observed in vivo but substitutions at positions 103, 106, 108, 181, 188 and 190 have been also observed in the RT region. The K103N mutation is the most efavirenz random access mutations in the RT  region of HIV-1 where as the other  efavirenz mutations at positions 100, 106, 108, 181, 188, 190 and 225  affect the  amino acid positions in the RT gene of HIV-1 [58,59]. The most random access Mutations found in the delavirdine resistant virus occurs at codon positions 103 and 181[60]. Rilpivirine resistance associated mutations  like K101E, K101P, E138A, E138G, E138K,E138Q, V179L, Y181C, Y181I ,Y181V, H221Y, F227C, M230L, K101E/M184I  were reported[ 61] .Rilpivirane is mainly effective towards the drug resistance mutations K103N generated by first generation NNRTIs. The sixteen mutations are  associated with resistance to rilpivirine are K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L.The risk of virological failure in HIV-1 infected patients is due to the above mutations. The most common resistance mutations that emerge against rilpivirine is E138K[ 62].

The drug resistance mutations developed in slower rate in the presence of didanosine. The most common resistance associated mutations is L74V observed in vivo in the viral pol gene which confers cross resistance to zalcitabine. The other mutations observed include K65R and M184V in the presence of didanosine. The T69D is the most common zalcitabine drug resistance associated mutation observed in vivo. The zalcitabine resistance mutations at positions 65, 74, 75, 184 and 215 in the pol gene were observed rarely without any cross resistance to other NRTIs[ 63].The didanosine, zidovudine and zalcitabine was tested among the people with advanced HIV disease . The survival rate was longer in patients those were switched over zidovudine to zalcitabine but no longer survival among patients who were treated with didanosine[ 64].

The reverse transcriptase mutations responsible for the most nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors.The Two novel mutations Q145M/L have been reported to cause high level resistance to multiple nucleoside reverse transcriptase inhibitors i.e. zidovudine, lamivudine, stavudine, didanosine, tenfovir and abacavir as well as both non-nucleoside reverse transcriptase inhibitors i.e. nevirapine and efavirenz in both cell culture and enzymatic assays[ 65].Sometimes, a rare mutation in the HIV-1 reverse transcriptase cause drug resistance mutation, which confer high level resistance to the non-nucleoside reverse transcriptase inhibitors. A mutation I 132M which confers high level resistance to the non-nucleoside reverse transcriptase inhibitors nevirapine and delavirdine but is hyper-susceptibility nucleoside reverse transcriptase inhibitors lamivudine and tenfovir [66]. Mutation in the Reverse transcriptase of HIV-1 have a substantial impact on drug resistance phenotype and replication capacity. The introduction of mutation in the M184V in the reverse transcriptase of HIV-1 has a reduced susceptibility to abacavir, lamivudine and didanosine but increased susceptibility to zidovudine, stavudine and tenofovir. The replication capacity of the virus also decrease in the presence of this M184V mutation.

Similarly L74 V mutation in the reverse transcriptase of HIV-1 decreased the susceptibility  to abacavir, lamivudine and didanosine but increased susceptibility to zidovudine and tenfovir. K101E and G190S decrease susceptibility to all nucleoside reverse transcriptase inhibitors but the K103N mutation had little effect on the susceptibility towards the nucleoside reverse transcriptase inhibitors. In some strains K101E, G190S, L74V mutation increased the replication capacity in the presence of non-nucleoside reverse transcriptase inhibitors but has the decreased replication capacity in the absence of non-nucleoside reverse transcriptase inhibitors [67]. A single mutation T215S persist in MSM group treatment naive population in Croatia and this mutation persists in a cluster of population those are taking NRTIs [68]. The monitoring and drug resistance testing is essential before initiation of antiretroviral therapy are recommended to facilitate the selection of appropriate ART. The HIV-1 drug resistance mutations were characterized among the drug naive HIV-1 infected patients and the reverse transcriptase inhibitor mutations A62V, K103N, Y181C were found in Northern Vietnam population[ 69].

Resistance to antiretroviral therapy is associated with mortality. The risk of emerging resistance mutations to first line therapy is important for both resource rich settings and resource poor settings. The patients with thymidine associated mutations confers high level resistance to zidovudine and stavudine.The patients with K65R mutation is associated with multiple nucleoside reverse transcriptase inhibitors like tenfovir, abacavir and didanosine [70].The detection of mutations in early virologic failure in HIV-1 infected patients followed by antiretroviral therapy in the treatment naive patients is very critical.Such mutations are undetectable at baseline by population sequencing. The key mutations K65R, K103N,Y181C, M184V and M184I developed against lamivudine, tenfovir, nevirapine and efavirenz in the reverse transcriptase region were quantified by allele specific chain reaction [71].Structural, biochemical and genetic analysis showed that some group of non-nucleoside inhibitors bind to the hydrophobic pocket near the polymerase active site. Mutations in the hydrophobic sites of the amino acids in the reverse transcriptase region developed the drug resistance mutations towards the non-nucleoside reverse transcriptase inhibitors. The hydrophobic amino acid pocket like tyrosine 181, tyrosine 188 or lysine 103 leads to resistant to the non-nucleoside reverse transcriptase inhibitors [72].The HIV-1 pol gene diversity among the Brazilian patients those were taking nucleoside and non-nucleoside reverse transcriptase is the cause of drug resistance mutation in the reverse transcriptase region. The similar kind of reverse transcriptase nucleoside resistance mutations M41L (52%), D67N (30%), K70R (26%), M184V (88%), L210W (29%), T215Y/I/F (65%) and K219Q/E/N (28%) and reverse transcriptase non-nucleoside resistance mutation K103N (52%) were developed in all HIV-1 subtypes B, F and recombinant B/F viruses of Brazilian population[ 73].

In some patients, a single emergence of non-nucleoside reverse transcriptase associated drug resistance mutations in the reverse transcriptase region is a cause of treatment failure even the use of  nucleoside reverse transcriptase inhibitors unable to prevent the emergence of  the particular single mutation. The Y181C mutation in the reverse transcriptase region confers high level resistance mutations towards the non-nucleoside reverse transcriptase inhibitors but did not reduce or emerge the prevention of this Y181C mutation towards the nucleoside reverse transcriptase inhibitors [74]. The presence of base line mutations in the reverse transcriptase region associated with hyper susceptibility to non-nucleoside reverse transcriptase inhibitors.The base line mutations M41L, M184V, L210W and T215Y in the reverse .transcriptase gene is the cause of decrease viral load up to undetectable level [75]. The presence of the resistance associated mutations towards the first generation non-nucleoside reverse transcriptase inhibitors affect the replication kinetics of the virus and reduced the drug susceptibility even treated with second generation non-nucleoside reverse transcriptase inhibitors.In some patients K103N, M230L mutations in the reverse transcriptase gene containing viruses were severely impaired in replication capacity in the absence of NNRTIs. The K103N mutation containing viruses replicates well in the presence of efavirenz and nevirapine but the M230L mutation in the reverse transcriptase gene displayed substantial replication in the presence of all NNRTIs. The mutations K103N and M230L in the reverse transcriptase gene is associated with high level resistance to  first generation NNRTIs efavirenz and nevirapine while the K103N containing viruses remains susceptible  to second generation NNRTIs etravirine [76].The β3-β4 region in the reverse transcriptase gene of HIV-1 is associated drug resistance mutation. The point mutation, deletion and insertion in this region leads to development of drug resistance in the patients failing nucleoside reverse transcriptase therapy. The deletion or insertion in the Q151M site of β3-β4 region is associated with high level resistance towards NRTIs [77].The acquisition of thymidine associated mutations in the reverse transcriptase gene may lead to drug resistance towards zidovudine or didanosine. The N348I mutation  in the HIV-1 RT  associated with drug resistance mutation towards the other TAMs K70R, Y181C, L74V, M184V[ 78]. HIV-1 reverse transcriptase mutations in the connection   sub-domain (CN) and RNaseH domain of HIV-1 reverse transcriptase of the subtype -B. HIV-1 infected patients enhance the nucleoside and non-nucleoside reverse transcriptase.              &n bsp;                                 &nbs p;                &n bsp;             

The mutations A376S, A400T, Q334D, G335D, N348I and A371V   in the CN domain is associated with increased AZT resistance in the presence of thymidine analog mutations. The mutations L100I/ K103N/ Y181C in the CN domain enhanced the etravirine resistance in the treatment experienced Brazilian subtype C infected patients [79]. The 69 position deletion in the reverse transcriptase gene of HIV-1 confer high level resistance to nevirapine[80]. Etravirine is active against the drug resistance mutations K103N and Y181C in the RT region of HIV-1 [81].The non-nucleoside reverse transcriptase inhibitors etravirine and rilpivirine is conferred by E138K mutation in reverse transcriptase gene of the HIV-1. The mutations E138K/ M184I confer high level resistance to lamivudine and emtricitabine resistance in most patients with virologic failure. The replication capacity of the E138K/M184I mutant in the presence of etravirine was significantly higher than the E138K andE138K/M184V mutants of HIV-1 isolates. Thus, the replication capacity of the virus as well as the resistance associated mutations in the reverse transcriptase gene of HIV-1 infected patients were not similar in function associated with several nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors [82]. Tenfovir is the preferred regimen for adults and adolescents by WHO 2013 guidelines.Genotypically predicted level of drug resistance mutations pattern shown 65% opted for Tenfovir in case of south Indian population [83].


The mutations in the reverse transcriptase gene is the cause of treatment failure by the antiretroviral therapy. The antiretroviral therapy like nucleoside/nucleotide reverse transcriptase inhibitors are used by the patients is directly related with immunological conditions of the patient as well as the mutations in the reverse transcriptase gene of   human immuno-deficiency virus-1. The virologic failure is reported when the genotyping analysis has been done. The human immuno-deficiency virus drug resistance mutations was developed due to mutations in the reverse transcriptase gene associated nucleoside/nucleotide reverse transcriptase inhibitors that can be confirmed by genotypic and  phenotypic analysis. Only thing is to analyze the mutations in the reverse transcriptase gene during pre-treatment or treatment failure patients those are falling with antiretroviral therapy.

Acknowledgement: Thanks to the Director General of Indian Council of Medical Research for providing Senior Research Fellowship to Sushanta Kumar Barik.

Supplementary information: The author has competing no financial interest.



1.Greene WC. A history of AIDS: looking back to see ahead. European journal of immunology. 2007 Nov1;37(S1):S94-102.

2. Faria NR, Rambaut A, Suchard MA, Baele G, Bedford T, Ward MJ, Tatem AJ, Sousa JD, Arinaminpathy N, Pépin J, Posada D. The early spread and epidemic ignition of HIV-1 in human populations. Science. 2014 Oct 3;346(6205):56-61.

3.Ortblad KF, Lozano R, Murray CJ. The burden of HIV: insights from the Global Burden of Disease Study 2010. Aids. 2013 Aug 24;27(13):2003-17.

4.Watts JM, Dang KK, Gorelick RJ, Leonard CW, Bess Jr JW, Swanstrom R, Burch CL, Weeks KM. Architecture and secondary structure of an entire HIV-1 RNA genome. Nature. 2009 Aug 6;460(7256):711-6.

5. Ryalat ST, Sawair FA, Shayyab MH, Amin WM. The knowledge and attitude about HIV/AIDS among Jordanian dental students:(Clinical versus pre clinical students) at the University of Jordan. BMC research notes. 2011 Jun 15;4(1):1.

6. Kumarasamy N, Patel A, Pujari S. Antiretroviral therapy in Indian setting: When & what to start with, when & what to switch to?. The Indian journal of medical research. 2011 Dec 1;134(6):787.

7. Kozal MJ. Drug?resistant human immunodefiency virus. Clinical Microbiology and Infection. 2009 Jan 1;15(s1):69-73.

8. Chandy S, Singh G, Heylen E, Gandhi M, Ekstrand ML. Treatment switching in South Indian patients on HAART: what are the predictors and consequences?. AIDS care. 2011 May 1;23(5):569-77.

9. Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, Heneine W, Kantor R, Jordan MR, Schapiro JM, Vandamme AM. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PloS one. 2009 Mar 6;4(3):e4724.

10. Nazziwa J, Njai HF, Ndembi N, Birungi J, Lyagoba F, Gershim A, Nakiyingi-Miiro J, Nielsen L, Mpendo J, Nanvubya A, Debont J. HIV type 1 transmitted drug resistance and evidence of transmission clusters among recently infected antiretroviral-naive individuals from Ugandan fishing communities of Lake Victoria. AIDS Res Hum Retroviruses. 2013 May 1;29(5):788-95.

11. Wang X, He C, Xing H, Liao L, Xu X, He J, Liu Y, Ling H, Liang S, Hsi JH, Ruan Y. Short communication: emerging transmitted HIV type 1 drug resistance mutations among patients prior to start of first-line antiretroviral therapy in middle and low prevalence sites in China. AIDS research and human retroviruses. 2012 Dec 1;28(12):1637-9.

12. Grgic I, Lepej SZ, Lunar MM, Poljak M, Vince A, Vrakela IB, Planinic A, Seme K, Begovac J. The prevalence of transmitted drug resistance in newly diagnosed HIV-infected individuals in Croatia: the role of transmission clusters of men who have sex with men carrying the T215S surveillance drug resistance mutation. AIDS research and human retroviruses. 2013 Feb 1;29(2):329-36.

13. Avi R, Huik K, Pauskar M, Ustina V, Karki T, Kallas E, Jogeda EL, Krispin T, Lutsar I. Transmitted drug resistance is still low in newly diagnosed human immunodeficiency virus type 1 CRF06_cpx-infected patients in Estonia in 2010. AIDS research and human retroviruses. 2014 Mar 1;30(3):278-83.

14. Castro E, Zhao H, Cavassini M, Mullins JI, Pantaleo G, Bart PA. HIV-1 superinfection with a triple-class drug-resistant strain in a patient successfully controlled with antiretroviral treatment. AIDS. 2014 Jul 31;28(12):1840-4.

15. Pernas B, Grandal M, Mena A, Castro-Iglesias A, Cañizares A, Wyles DL, López-Calvo S, Pértega S, Rodríguez-Osorio I, Pedreira JD, Poveda E. High prevalence of subtype F in newly diagnosed HIV-1 persons in northwest Spain and evidence for impaired treatment response. AIDS. 2014 Jul 31;28(12):1837-40.

16. Kuhn L, Hunt G, Technau KG, Coovadia A, Ledwaba J, Pickerill S, Penazzato M, Bertagnolio S, Mellins CA, Black V, Morris L. Drug resistance among newly-diagnosed HIV-infected children in the era of more efficacious antiretroviral prophylaxis. AIDS (London, England). 2014 Jul 17;28(11):1673.

17. Huang H, Chopra R, Verdine GL, Harrison SC. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science. 1998 Nov27;282(5394):1669-75.

18. Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harbor perspectives in medicine. 2012 Apr 1;2(4):a007161.

19. Ruedy J, Schechter M, Montaner JS. Zidovudine for early human immunodeficiency virus (HIV) infection: who, when, and how?. Annals of internal medicine. 1990 May 15;112(10):721-3.

20. Gelmon K, Montaner JS, Fanning M, Smith JR, Falutz J, Tsoukas C, Gilll J, Wells G, O'Shaughnessy M, Wainberg M, Ruedy J. Nature, time course and dose dependence of zidovudine-related side effects: results from the Multicenter Canadian Azidothymidine Trial. Aids. 1989 Sep 1;3(9):555-62.

21. Horwitz JP, Chua J, Noel M, Donatti JT, Freisler J. Substrates for Cytochemical Demonstration of Enzyme Activity. II. Some Dihalo-3-indolyl Phosphates and Sulfates1. Journal of medicinal chemistry. 1966 May;9(3):447-.

22. Piscitelli SC, Kelly G, Walker RE, Kovacs J, Falloon J, Davey RT, Raje S, Masur H, Polis MA. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrobial agents and chemotherapy. 1999 Mar 1;43(3):647-50.

23. Somani PO, Khot A, Jain S, Shah D, Rathi PM. Stavudine induced multiple adverse effects in HIV-infected patient. Journal of Case Reports. 2013 Jun 20;3(1):186-90.

24. Robins MJ, McCarthy Jr JR, Robins RK. Purine Nucleosides. XII. The Preparation of 2', 3'-Dideoxyadenosine, 2', 5'-Dideoxyadenosine, and 2', 3', 5'-Trideoxyadenosine from 2'-Deoxyadenosine*. Biochemistry. 1966 Jan;5(1):224-31.

25. Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science. 1990 Sep 28;249(4976):1533-44.

26. Knupp CA, Graziano FM, Dixon RM, Barbhaiya RH. Pharmacokinetic-interaction study of didanosine and ranitidine in patients seropositive for human immunodeficiency virus. Antimicrobial agents and chemotherapy. 1992 Oct 1;36(10):2075-9.

27. Yarchoan R, Mitsuya H, Thomas RV, Pluda JM, Hartman NR, Perno CF, Marczyk KS, Allain JP, Johns DG, Broder S. In vivo activity against HIV and favorable toxicity pro?le of 2', 3'-dideoxyinosine. Science. 1989;245:412-5.

28. McNeely MC, Yarchoan R, Broder S, Lawley TJ. Dermatologic complications associated with administration of 2′, 3′-dideoxycytidine in patients with human immunodeficiency virus infection. Journal of the American Academy of Dermatology. 1989 Dec 31;21(6):1213-7.

29.Lazarus EM, Otwombe K, Fairlie L, Untiedt S, Violari A, Laher F, Evans D, Levin L. Lamivudine monotherapy as a holding strategy in HIV-infected children in South Africa. Journal of AIDS & Clinical Research. 2013 Nov 13;2013.

30. Modak D, Guha SK. Severe skin rash with lamivudine in HIV infected patients: Some unusual case reports. Indian journal of pharmacology. 2013 May;45(3):298.

31. Bapuji AT, Nagesh M, Ramaraju D, Syedba S, Kiran R, Ravinder S. A bioequivalence study comparing two formulation of emtricitabine capsules. Journal of Bioequivalence & Bioavailability. 2010 Jan 21;2010.

32. Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, Lafon S, Pearce G, Steel H. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clinical therapeutics. 2001 Oct 31;23(10):1603-14.

33.Cheng YC, Dutschman GE, Bastow KF, Sarngadharan MG, Ting RY. Human immunodeficiency virus reverse transcriptase. General properties and its interactions with nucleoside triphosphate analogs. Journal of Biological Chemistry. 1987 Feb 15;262(5):2187-9.

34. Arion D, Kaushik N, McCormick S, Borkow G, Parniak MA. Phenotypic mechanism of HIV-1 resistance to 3'-azido-3'-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry. 1998 Nov 10;37(45):15908-17.

35. Meyer PR, Matsuura SE, Tolun AA, Pfeifer I, So AG, Mellors JW, Scott WA. Effects of specific zidovudine resistance mutations and substrate structure on nucleotide-dependent primer unblocking by human immunodeficiency virus type 1 reverse transcriptase. Antimicrobial agents and chemotherapy. 2002 May 1;46(5):1540-5.

36. Boucher CA, O'Sullivan E, Mulder JW, Ramautarsing C, Kellam P, Darby G, Lange JM, Goudsmit J, Larder BA. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. Journal of Infectious Diseases. 1992 Jan 1;165(1):105-10.

37. Praparattanapan J, Kotarathitithum W, Chaiwarith R, Nuntachit N, Sirisanthana T, Supparatpinyo K. Resistance-associated mutations after initial antiretroviral treatment failure in a large cohort of patients infected with HIV-1 subtype CRF01_AE. Current HIV research. 2012 Dec 1;10(8):647-52.

38. Kellam P, Boucher CA, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proceedings of the National Academy of Sciences. 1992 Mar 1;89(5):1934-8.

39. Harrigan PR, Kinghorn I, Bloor S, Kemp SD, Najera I, Kohli A, Larder BA. Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility. Journal of virology. 1996 Sep 1;70(9):5930-4.

40.Bacheler LT, Anton ED, Kudish P, Baker D, Bunville J, Krakowski K, Bolling L, Aujay M, Wang XV, Ellis D, Becker MF. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrobial agents and chemotherapy. 2000 Sep 1;44(9):2475-84.

41. Marcelin AG, Delaugerre C, Wirden M, Viegas P, Simon A, Katlama C, Calvez V. Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure. Journal of medical virology. 2004 Jan 1;72(1):162-5.

42. Quan Y, Gu Z, Li X, Li Z, Morrow CD, Wainberg MA. Endogenous reverse transcription assays reveal high-level resistance to the triphosphate of (-) 2'-dideoxy-3'-thiacytidine by mutated M184V human immunodeficiency virus type 1. Journal of virology. 1996 Aug 1;70(8):5642-5.

43. White KL, Chen JM, Feng JY, Margot NA, Ly JK, Ray AS, MacArthur HL, McDermott MJ, Swaminathan S, Miller MD. The K65R reverse transcriptase mutation in HIV-1 reverses the excision pheno type of zidovudine resistance mutations. Antiviral therapy. 2006 Jan 1;11(2):155.

44. De Clercq E. Non?nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV?1) infections: Strategies to overcome drug resistance development. Medicinal research reviews. 1996 Mar 1;16(2):125-57.

45. Pauwels R, Andries K, Debyser Z, Kukla MJ, Schols D, Breslin HJ, Woestenborghs R, Desmyter J, Janssen MA, De Clercq E. New tetrahydroimidazo [4, 5, 1-jk][1, 4]-benzodiazepin-2 (1H)-one and-thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2', 3'-dideoxynucleoside analogs. Antimicrobial agents and chemotherapy. 1994 Dec 1;38(12):2863-70.

46. Lamson MJ, Sabo JP, Macgregor TR, Pav JW, Rowland L, Hawi A, Cappola M, Robinson P. Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers. Biopharmaceutics & drug disposition. 1999 Sep 1;20(6):285-91.

47. Ouyang DW et al. (2010) Lack of increased hepatotoxicity in HIV-infected pregnant women receiving nevirapine compared with other antiretrovirals. AIDS 24:109-114 .

48. McDonagh EM, Lau JL, Alvarellos M, Altman RB, Klein TE. PharmGKB Summary: Efavirenz Pathway, Pharmacokinetics (PK). Pharmacogenetics and genomics. 2015 Jul;25(7):363.

49. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer III WA, Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. New England Journal of Medicine. 2004 Apr 29;350(18):1850-61.

50. Shelton MJ, Hewitt RG, Adams J, Della-Coletta A, Cox S, Morse GD. Pharmacokinetics of ritonavir and delavirdine in human immunodeficiency virus-infected patients. Antimicrobial agents and chemotherapy. 2003 May 1;47(5):1694-9.

51. Demeter LM, Shafer RW, Meehan PM, Holden-Wiltse J, Fischl MA, Freimuth WW, Para MF, Reichman RC. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrobial agents and chemotherapy. 2000 Mar 1;44(3):794-7.

52. de Béthune MP. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009). Antiviral research. 2010 Jan 31;85(1):75-90.

53. Schöller-Gyüre M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clinical pharmacokinetics. 2009 Sep 1;48(9):561-74.

54. Martinez E, Nelson M. Simplification of antiretroviral therapy with etravirine. AIDS Rev. 2010 Jan 1;12(1):52-9.

55. Azijn H, Tirry I, Vingerhoets J, de Béthune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrobial agents and chemotherapy. 2010 Feb 1;54(2):718-27.

56. Bangsberg DR, Ragland K, Monk A, Deeks SG. A single tablet regimen is associated with higher adherence and viral suppression than multiple tablet regimens in HIV+ homeless and marginally housed people. AIDS (London, England). 2010 Nov 27;24(18):2835.

57. Charpentier C, Lambert-Niclot S, Visseaux B, Morand-Joubert L, Storto A, Larrouy L, Landman R, Calvez V, Marcelin AG, Descamps D. Evolution of the K65R, K103N and M184V/I reverse transcriptase mutations in HIV-1-infected patients experiencing virological failure between 2005 and 2010. Journal of Antimicrobial Chemotherapy. 2013 Oct 1;68(10):2197-8.

58. Hirsch MS, Günthard HF, Schapiro JM, Vézinet FB, Clotet B, Hammer SM, Johnson VA, Kuritzkes DR, Mellors JW, Pillay D, Yeni PG. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clinical Infectious Diseases. 2008 Jul 15;47(2):266-85.

59. Bacheler L, Jeffrey S, Hanna G, D'Aquila R, Wallace L, Logue K, Cordova B, Hertogs K, Larder B, Buckery R, Baker D. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. Journal of virology. 2001 Jun 1;75(11):4999-5008.

60. Demeter LM, Meehan PM, Morse G, Gerondelis P, Dexter A, Berrios L, Cox S, Freimuth W, Reichman RC. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. JAIDS Journal of Acquired Immune Deficiency Syndromes. 1997 Feb 1;14(2):136-44.

61. Anta L, Llibre JM, Poveda E, Blanco JL, Alvarez M, Pérez-Elías MJ, Aguilera A, Caballero E, Soriano V, de Mendoza C, Resistance Platform of the Spanish AIDS Research Network. Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies. AIDS. 2013 Jan 2;27(1):81-5.

62. Imaz A, García F, di Yacovo S, Llibre JM. [Resistance profile of rilpivirine]. Enfermedades infecciosas y microbiologia clinica. 2013 Jun;31:36-43.

63. Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs. 1996 Aug 1;52(2):168-85.

64. Saravolatz LD, Winslow DL, Collins G, Hodges JS, Pettinelli C, Stein DS, Markowitz N, Reves R, Loveless MO, Crane L, Thompson M. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. New England Journal of Medicine. 1996 Oct 10;335(15):1099-106.

65. Varghese V, Mitsuya Y, Shahriar R, Bachmann MH, Fessel WJ, Kagan RM, Shafer RW. Human immunodeficiency virus type 1 isolates with the reverse transcriptase (RT) mutation Q145M retain nucleoside and nonnucleoside RT inhibitor susceptibility. Antimicrobial agents and chemotherapy. 2009 May 1;53(5):2196-8.

66.Ambrose Z, Herman BD, Sheen CW, Zelina S, Moore KL, Tachedjian G, Nissley DV, Sluis-Cremer N. The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistance mutation I132M confers hypersensitivity to nucleoside analogs. Journal of virology. 2009 Apr 15;83(8):3826-33.

67. Trivedi V, Von Lindern J, Montes-Walters M, Rojo DR, Shell EJ, Parkin N, O'Brien WA, Ferguson MR. Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility. AIDS research and human retroviruses. 2008 Oct 1;24(10):1291-300.

68. Grgic I, Lepej SZ, Lunar MM, Poljak M, Vince A, Vrakela IB, Planinic A, Seme K, Begovac J. The prevalence of transmitted drug resistance in newly diagnosed HIV-infected individuals in Croatia: the role of transmission clusters of men who have sex with men carrying the T215S surveillance drug resistance mutation. AIDS research and human retroviruses. 2013 Feb 1;29(2):329-36.

69. Phan TT, Ishizaki A, Phung DC, Bi X, Oka S, Ichimura H. Characterization of HIV type 1 genotypes and drug resistance mutations among drug-naive HIV type 1-infected patients in Northern Vietnam. AIDS research and human retroviruses. 2010 Feb 1;26(2):233-5.

70. Gupta R, Hill A, Sawyer AW, Pillay D. Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. Clinical infectious diseases. 2008 Sep 1;47(5):712-22.

71. Metzner KJ, Giulieri SG, Knoepfel SA, Rauch P, Burgisser P, Yerly S, Gunthard HF, Cavassini M. Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and-adherent patients. Clinical infectious diseases. 2009 Jan 15;48(2):239-47.

72. Loya S, Bakhanashvili M, Tal R, Hughes SH, Boyer  PL, Hiz A. Enzymatic properties of two mutants of reverse transcriptase of human immunodeficiency virus type 1 (tyrosine 181→ isoleucine and tyrosine 188→ leucine), resistant to nonnucleoside inhibitors. AIDS research and human retroviruses. 1994 Aug;10(8):939-46.

73. de Sa-Filho DJ, Soares MD, Candido V, Gagliani LH, Cavaliere E, Diaz RS, Caseiro MM. HIV type 1 pol gene diversity and antiretroviral drug resistance mutations in Santos, Brazil. AIDS research and human retroviruses. 2008 Mar 1;24(3):347-53.

74. Demeter LM, Meehan PM, Morse G, Gerondelis P, Dexter A, Berrios L, Cox S, Freimuth W, Reichman RC. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. JAIDS Journal of Acquired Immune Deficiency Syndromes. 1997 Feb 1;14(2):136-44.

75. Tozzi V, Zaccarelli M, Narciso P, Trotta MP, Ceccherini-Silberstein F, De Longis P, D'offizi G, Forbici F, D'arrigo R, Boumis E, Bellagamba R. Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort. Journal of Infectious Diseases. 2004 May 1;189(9):1688-95.

76. Xu HT, Oliveira M, Quan Y, Bar-Magen T, Wainberg MA. Differential impact of the HIV-1 non-nucleoside reverse transcriptase inhibitor mutations K103N and M230L on viral replication and enzyme function. Journal of antimicrobial chemotherapy. 2010 Nov 1;65(11):2291-9.

77. Winters MA, Coolley KL, Cheng P, Girard YA, Hamdan H, Kovari LC, Merigan TC. Genotypic, phenotypic, and modeling studies of a deletion in the β3-β4 region of the human immunodeficiency virus type 1 reverse transcriptase gene that is associated with resistance to nucleoside reverse transcriptase inhibitors. Journal of virology. 2000 Nov 15;74(22):10707-13.

78. Radzio J, Yap SH, Tachedjian G, Sluis-Cremer N. N348I in reverse transcriptase provides a genetic pathway for HIV-1 to select TAMs and mutations antagonistic to TAMs. AIDS (London, England). 2010 Mar 13;24(5):659.

79. Delviks-Frankenberry KA, Lengruber RB, Santos AF, Silveira JM, Soares MA, Kearney MF, Maldarelli F, Pathak VK. Connection subdomain mutations in HIV-1 subtype-C treatment-experienced patients enhance NRTI and NNRTI drug resistance. Virology. 2013 Jan 20;435(2):433-41.

80. Suzuki K, Kaufmann GR, Mukaide M, Cunningham P, Harris C, Leas L, Kondo M, Imai M, Pett SL, Finlayson R, Zaunders J. Novel deletion of HIV type 1 reverse transcriptase residue 69 conferring selective high-level resistance to nevirapine. AIDS research and human retroviruses. 2001 Sep 1;17(13):1293-6.

81. Xu H, Quan Y, Brenner BG, Bar-Magen T, Oliveira M, Schader SM, Wainberg MA. Human immunodeficiency virus type 1 recombinant reverse transcriptase enzymes containing the G190A and Y181C resistance mutations remain sensitive to etravirine. Antimicrobial agents and chemotherapy. 2009 Nov 1;53(11):4667-72.

82. Hu Z, Kuritzkes DR. Interaction of reverse transcriptase (RT) mutations conferring resistance to lamivudine and etravirine: effects on fitness and RT activity of human immunodeficiency virus type 1. Journal of virology. 2011 Nov 1;85(21):11309-14.

83. Dinesha TR, Gomathi S, Boobalan J, Sivamalar S, Solomon SS, Pradeep A, Poongulali S, Solomon S, Balakrishnan P, Saravanan S. Genotypic HIV-1 Drug Resistance Among Patients Failing Tenofovir-Based First-Line HAART in South India. AIDS Research and Human Retroviruses. 2016 Jul 14.

Source(s) of Funding

Indian Council of Medical Research,Govt. of India

Competing Interests

The author has competing no financial interest

0 reviews posted so far

0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.


Author Comments
0 comments posted so far


What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)