Drug Profile Of Raltegravir - An Integrase Iinhibitor

HIV is a chronic viral infection which over time reduces a person's defence system and makes them more likely to catch infections.

This reduction in the effectiveness of the defense system can lead to the symptoms known as AIDS.

Infection with HIV can occur because of;

• contact with infected blood (such as sharing needles)
• having sex with an infected person
• Or being born to an HIV infected mother.

The chance of catching HIV from needles is around 5 times more likely than having sex with someone infected with HIV. There is no difference in your chance of catching HIV from needles depending upon whether you are male or female.

AIDS stands for Acquired Immune Deficiency Syndrome and was first described in    1981. The virus causing AIDS (called Human Immunodeficiency Virus or HIV ) was found in 1983 and a test was developed to detect it in 1985.

AIDS occurs when infection with HIV has weakened the bodies defensive system (called the immune system) leading to unusual infections and cancers , Such as Pneumocystitis carinii pneumonia or PCP , Candida oesophagitis -   a fungal infection of the gullet, Cytomegalovirus (CMV) infection of the retina, Mycobacterial infection of the blood, Malignancies (tumors or cancers). There are other infections that can occur in AIDS but usually less frequently. Some patients may develop problems with brain function known as HIV dementia

It may occur within 2 years of infection with HIV in around 5% of cases but generally it takes longer. By about 10 years after infection 50% of patients have developed AIDS. How long it will take the other 50%, and whether everyone infected with HIV will develop AIDS is not as yet known since doctors have not been able to follow patients with HIV for much longer than around 15 years.

Once AIDS has developed further weakening of the immune system occurs. In an experienced centre around 60% of patients with AIDS survive one year, 40% two years, 20% three years, 5-10% four years and less than 5% five years. There are some drugs (called anti-retroviral or anti HIV drugs ) that are able to slow the infection with HIV down and delay the onset of AIDS. They also increase an individual’s chance of staying alive. There are a number of drugs that have been shown to have some effect on HIV. These drugs have various names such as anti-HIV therapy, anti-retroviral drugs, or just viral chemotherapy.

The most well known drug is AZT also known as Zidovudine or Retrovir. Other similar drugs now available are DDI (Videx or didansosine) and DDC (Hivid or zalcitabine), 3TC (Epivir or lamivudine), D4T (Zerit or stavudine). These are all drugs known as nucleoside analogues, nucleoside reverse transcriptase inhibitors (NRTIs). AZT is taken two or three times per day as a capsule. Reduced doses may be needed depending on weight and certain other drugs such as methadone. Drugs like AZT, DDC and DDI stop the virus making new DNA - the genetic code needed to make new viruses. Reverse transcriptase is an important enzyme used in making new virus. It works by reading the viral RNA and making a DNA copy using nucleosides (the building blocks of RNA or DNA). Nucleoside analogues such as AZT interfere with the working of reverse transcriptase. This interferes with the production of new virus.

A number of non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been introduced. They work in exactly the same way as NRTIs but are not nucleoside analogues. Another group of drugs known as protease inhibitors (PIs) have been shown to be very effective. They work by inhibiting or interfering with the viral protease enzyme which is necessary to produce new virus.¹

Raltegravir

Raltegravir (isentress) is an antiretroviral drug produced by Merck & Co, used to treat HIV infection. It received FDA approval in October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval.

Chemistry  of Raltegravir

ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N-[(4-Fluorophenyl) methyl]-1, 6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1, 3, 4-oxadiazol-2-yl) carbonyl] amino] ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt.

Raltegravir structure

The empirical formula is C₂₀H₂₀FKN₆O₅    Molecular weight is 482.51

Drug Description of Raltegravir

Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol.

Each film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol ) and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant ), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol , titanium dioxide, polyethylene glycol 3350, talc , red iron oxide and black iron oxide.²

Mechanism of action of Raltegravir^{3, 4}

The mechanism of action of raltegravir involves integrase which is an enzyme necessary for the HIV virus to successfully insert its viral DNA into a human host’s DNA. The virus must be able to carry out this process in order to use the host’s cellular machinery to make copies of its viral DNA in order to successfully spread the HIV infection. Integrase inhibitors, like raltegravir, block the action of integrase and prevent the HIV virus from successfully inserting its DNA into the host DNA. Raltegravir essentially blocks HIV before it can even alter human genetic material. Human cells lack the integrase enzyme, thus toxicity and side effects to human cells is expected to be low.

Efficacy

In a study of the drug as part of combination therapy, raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides.^{5, 6}

Research

Raltegravir significantly alters HIV viral dynamics and decay and further research in this area is ongoing. In clinical trials patients taking Raltegravir achieved viral loads less then 50 copies per millitre sooner then those taking similarly potent Non-nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors. This statistically significant difference in viral load reduction has caused some HIV researchers to begin questioning long held paradigms about HIV viral dynamics and decay.⁷ Research into Raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.⁸

Pharmacology of Raltegravir

Administration of raltegravir following a high-fat meal increased the raltegravir area under the concentration-time curve (AUC) by approximately 19%. A high-fat meal slowed the rate of absorption, resulting in an approximately 34% decrease in the maximum plasma concentration (Cmax), an 8.5-fold increase in the plasma concentration at 12 hours, and a delay in the time to maximum concentration (Tmax) following a single 400 mg dose.

The effect of consumption of a range of food types on steady-state raltegravir pharmacokinetics (PK) is not known. Raltegravir was administered without regard to food in pivotal safety and efficacy studies of HIV-infected patients.

With twice-daily dosing, PK steady state is achieved within approximately the first 2 days of dosing. Considerable variability was observed in the PK of raltegravir in clinical trials. Among study participants receiving 400 mg twice-daily raltegravir, drug exposures were characterized by a geometric mean AUC within the first 12 hours of 14.3 mcM (hr) and a plasma concentration at 12 hours of 142 nM. The absolute bioavailability of raltegravir has not been established.⁹

Pharmacokinetics of Raltegravir

Absorption

Raltegravir is absorbed with a Tmax of approximately 3 hours post dose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C_12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C_12hr ranged from approximately 1.2 to 1.6.

The absolute bioavailability of raltegravir has not been established. In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC_0-12hr of 14.3 µM•hr and C_12hr of 142 nM.Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C_12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.

Distribution

Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.

Metabolism and Excretion

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radio labeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine , respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.²

Adverse effects

In Phase II studies, the most commonly reported treatment-related adverse effects were diarrhea, nausea, fatigue, headache, and itching. Other reported adverse effects included constipation, flatulence, and sweating. Overall, raltegravir was well tolerated, and its adverse effects were comparabl e to those in the placebo group. ^{10, 11} in the second part of one Phase II study, the most common adverse effects occurring after 24 weeks of treatment were headache, dizziness, and nausea. Eight serious, nondrug-related adverse effects occurred overall (7/160 in the raltegravir arm and 1/38 in the efavirenz arm); one patient taking twice-daily raltegravir 600 mg discontinued treatment because of elevated liver function tests. Drug-related clinical adverse events were less common with raltegravir than with efavirenz.¹²
Raltegravir has been generally well tolerated in ongoing Phase III studies (BENCHMRK-1 and -2) as well. The most common adverse effects of all intensities, regardless of causality, reported in treatment-experienced adult study participants so far include diarrhea, nausea, headache, and pyrexia.^13,14 Additionally, Grade 2 to 4 creatine kinase laboratory abnormalities were observed in clinical trial participants treated with raltegravir.¹⁵ The manufacturer notes that because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect rates observed in practice.¹⁶
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy; this may include raltegravir-containing regimens. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, (e.g., Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.¹⁷

Indications of Raltegravir

Raltegravir (ISENTRESS) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults.

The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients.

There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.²

Food and drug interactions of Raltegravir

Based on the results of drug interaction studies and clinical trials data, no dose adjustment of raltegravir is required when raltegravir is co administered with antiretroviral agents. ¹⁴ The addition of enfuvirtide to a raltegravir-containing regimen appears to increase virologic response. At Week 24 analysis of one dose-ranging study conducted in treatment-experienced, HIV infected participants, viral load decreased to less than 400 copies/ml in 60% of participants receiving raltegravir monotherapy and in 90% of patients receiving combined raltegravir and enfuvirtide.¹⁸

Raltegravir should be used with caution when administered with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1, including rifampin. These inducers of UGT1A1 may reduce plasma concentrations of raltegravir.¹⁶ Similar to rifampin; ritonavir-boosted tipranavir reduces plasma concentrations of raltegravir. However, in clinical trials, comparable efficacy of raltegravir was observed in this treatment group when compared with study participants not receiving ritonavir-boosted tipranavir.¹⁹
Drugs that inhibit UGT1A1 may increase plasma levels of raltegravir. Clinical trial data suggested that concomitant use of raltegravir and atazanavir (a strong inhibitor of UGT1A1) boosted with ritonavir caused increased plasma concentrations of raltegravir. However, this increase was not significant enough to warrant dose adjustment when co administering raltegravir and atazanavir.Raltegravir may be taken with or without food.²⁰

Effect of Raltegravir on the Pharmacokinetics of Other Agents

Raltegravir does not inhibit (IC₅₀ > 100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC₅₀ > 50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, methadone , opioid analgesics, statins , azole antifungal, proton pump inhibitors, oral contraceptives, and anti-erectile dysfunction agents).

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: lamivudine, tenofovir.

Effect of Other Agents on the Pharmacokinetics of Raltegravir

Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, caution should be used when coadministering ISENTRESS with rifampin or other strong inducers of UGT1A1]. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Other less strong inducers (e.g., efavirenz, nevirapine, rifabutin, St. John's wort) may be used with the recommended dose of ISENTRESS.

Similar to rifampin, tipranavir/ritonavir reduces plasma concentrations of ISENTRESS. However, approximately 100 subjects received raltegravir in combination with tipranavir/ritonavir in Protocols 018 and 019. Comparable efficacy was observed in this subgroup relative to subjects not receiving tipranavir/ritonavir. Based on these data, tipranavir/ritonavir may be co administered with ISENTRESS without dose adjustment of ISENTRESS.

Atazanavir, a strong inhibitor of UGT1A1, and atazanavir/ritonavir increase plasma concentrations of raltegravir. However, concomitant use of ISENTRESS and atazanavir/ritonavir did not result in a unique safety signal in Protocol 005 and Protocols 018 and 019. Based on these data, atazanavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.

Co administration of ISENTRESS with other drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.²

Warnings and precautions of Raltegravir

Patients should be informed that ISENTRESS is not a cure for HIV infection or AIDS. They should also be told that people taking ISENTRESS may still get infections or other conditions common in people with HIV (opportunistic infections). In addition, patients should be told that the long-term effects of ISENTRESS are not known at this time. Patients should also be told that it is very important that they stay under a physician's care during treatment with ISENTRESS.

Patients should be informed that ISENTRESS does not reduce the chance of passing HIV to others through sexual contact, sharing needles, or being exposed to blood. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms or other barrier methods to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should also be advised to never re-use or share needles.

Physicians should instruct their patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not take two tablets of ISENTRESS at the same time.

Physicians should instruct their patients to read the Patient Package Insert before starting ISENTRESS therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.²

Fertility And Pregnancy

No effect on fertility was seen in male or female rats at raltegravir doses up to 600 mg/kg/day, which resulted in an exposure 3-fold greater than the exposure seen with the recommended human dose.

Raltegravir is in FDA Pregnancy Category C. No adequate or well-controlled studies of raltegravir have been done in pregnant women. Also, no PK studies have been conducted to date in pregnant women. In animal studies, no treatment-related effects on embryonic/fetal survival or fetal weight were observed in rabbits (up to 1000 mg/kg/day) or rats (up to 600 mg/kg/day) receiving up to 3- to 4-fold the exposure at the recommended human dose. No treatment-related external, visceral, or skeletal changes were observed in rabbits.

Raltegravir should be used during pregnancy only if clearly needed. To monitor maternal and fetal outcomes of pregnant women exposed to raltegravir and other antiretroviral agents, physicians may access an Antiretroviral Pregnancy Registry.

It is not known whether raltegravir or its metabolites are distributed in human breast milk; however, raltegravir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and serious adverse reactions in nursing infants, HIV positive mothers should not breast-feed their infants if they are taking raltegravir.⁹

Manufacturer Information of Raltegravir

Isentress.⁹
Merck & Company, Inc
One Merck Dr
P.O. Box 100
Whitehouse Station, NJ 08889-0100
(800) 609-4618

Dosing information

Mode of Delivery

Oral.¹⁴

Dosage Form

Tablets containing raltegravir 400 mg. ²¹

The recommended dose of raltegravir in treatment-experienced HIV-infected adults is one 400-mg tablet twice daily.²⁰ No dosage adjustment is necessary in patients with mild to moderate hepatic or severe renal impairment.²²

Raltegravir 100, 200, 400, or 600 mg taken every 12 hours and given for up to 48 weeks was previously studied in a Phase II trial.¹²

Storage

Store tablets at a controlled room temperature of 20 C to 25 C (68 F to 77 F); excursions are permitted to 15 C to 30 C (59 F to 86 F).²¹

Brand name²

Isentress.

Clinical studies

New Antiretroviral

Raltegravir (MK-0518) Phase 3 trials show successful viral suppression in multi-drug resistant patients

The most important results at the 2007 conference were the late breaker abstracts from the newly-named integrase inhibitor raltegravir (formerly MK-0518). Based on early potency in experienced and naive patients in the Phase 2 dose finding studies seen last year. MK-0518 rolled out an early access programme in order to also be able to provide additional safety data as part of the regulatory submission. This fast-track application and early access, prior to results from Phase 3 studies, indicated the potential and excitement generated by this new compound.

At CROI, David Cooper and Roy Steigbigel presented 16-week results from the Phase 3 BENCHMRK-1 (Europe, Asia/Pacific, and Peru) and BENCHMRK-2 (US,Canada and South America) studies. Both studies had the same design and similar patient characteristics and results, which were largely combined for these presentations.

Approximately 350 three-class resistant patients on failing therapy enrolled in each study. Patients optimized their background regimen (OBT) based on treatment history and resistance tests, and were randomized 2:1 to add raltegravir 400mg twice daily or placebo. Primary endpoints included viral load, CD4 and tolerability at week 16, after which patients could receive open-label raltegravir (RGV)

The researchers concluded that raltegravir demonstrated potent and superior antiretroviral activity" compared with placebo in combination with optimized background therapy in patients with triple-class resistant HIV.

Using RGV with T-20 and DRV (darunavir) reduced viral load to <400 copies/mL in 98% of these highly treatment experienced patients.Raltegravir’s resistance barrier may be slightly higher than NNRTIs (Non nucleotide reverse transcriptase inhibitors) but it is not as resilient as protease inhibitors and mutations rapidly accumulated over 16 weeks in nearly three quarters of those people who failed to achieve viral suppression. ^{23, 24}

Raltegravir approved in Canada

In clinical trials with treatment-experienced PHAs, raltegravir, when used as part of combination therapy for one year, helped suppress production of HIV and raise levels of important T-cells in the blood. In these trials, raltegravir was found to be generally safe. Longer studies with raltegravir are underway and this drug is also being tested in people new to HIV therapy.²⁵

Integrase is a vital enzyme needed by HIV to hijack cells of the immune system and turn them into mini virus factories. Raltegravir works by slowing down or inhibiting the effects of integrase, reducing or stopping production of new HIV. Like all other approved medications, raltegravir must be taken as part of combination therapy. Raltegravir is taken at a dose of 400 mg twice daily, with or without food. Raltegravir is not a cure for HIV/AIDS.⁵

Raltegravir is the first approved medication in a new class of anti-HIV drugs called integrase inhibitors. Because there is an urgent need for novel anti-HIV therapies, Health Canada conducted an expedited review of raltegravir. Currently, there are five other classes of approved medications for the treatment of HIV infection, as follows:

Nucleoside analogues (nukes)

Non-nukes (NNRTIs)

Protease inhibitors

Fusion inhibitor

Entry inhibitor

When used in combination, these drugs are usually effective. However, HIV can develop mutations that allow it to resist the effects of these drugs. This is why the ongoing discovery and development of new-anti-HIV agents is important. Raltegravir has antiviral activity against strains of HIV that are resistant to currently licensed medications.^{3, 26}

Conclusion

Raltegravir: opening the road for integrase inhibitors in clinical practice

In the developed world, access to highly active antiretroviral therapy has led to a significant reduction in morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of resistant HIV-1 strains and the limitations of currently available classes of antiretroviral in terms of tolerance or toxicity highlight the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle requires the integration of cDNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. Raltegravir, the first integrase inhibitor, acts specifically to block the strand transfer step. In clinical trials, raltegravir has been shown to be a potent drug with a good pharmacokinetic and side-effect profile, both in treatment-naive and -experienced patients, and has achieved high rates of virological suppression even in those with limited treatment options. Raltegravir was approved by the US FDA in October 2007 and by the European Commission in December 2007 to be used in combination therapy in previously treated HIV-1-infected individuals.²⁷

References:

1. www.link.med.ed.ac.uk, HIV and aids introduction

2. www.rxlist.com , Rxlist, Raltegravir. The internet drug index

3.Grinstein, Beatriz et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir  (MK-0518) in treatment-experienced patients with multi-drug resistant virus: a phase II  randomized controlled trial. The Lancet. April 2007. 369: 1261-1269.

4.  AIDSMEDS.com 7 August 2007.
http://www.aidsmeds.com/archive/MK-0518_1639.shtml

5. Markowitz M, Nguyen BY, Gotuzzo E, et al (2007). " Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study ". J. Acquir. Immune Defic. Syndr. 46 (2): 125–33. doi: 10.1097/QAI.0b013e318157131c . PMID 17721395.

6. Stephenson J (2007). " Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus ". JAMA 297 (14): 1535–6. doi: 10.1001/jama.297.14.1535 . PMID 17426263.

7. Faster Viral Decay with Raltegravir - The Body

8. Impact of MK-0518 (Raltegravir) Intensification on HIV-1 Viral Latency in Patients   with Previous Complete Viral Suppression - Full Text View - ClinicalTrials.gov

9. www.hivanhepatitis.com , Raltegravir (isentress) overview.29.1.08

10. HIV and Hepatitis.com - Merck Announces Interim Results from Phase II Study of    MK-0518, an Investigational Oral HIV Integrase Inhibitor. Available at:  http://www.hivandhepatitis.com/2006icr/croi/docs/021006_b.html. Accessed 06/30/08 .

11.   Natap.org - Conference Reports: 10th European AIDS Conference. MK-0518, the    First Integrase Inhibitor for HIV, No Blarney . Available at: http://www.natap.org/2005/EACS/eacs_3.htm. Accessed 06/30/08 .

12.  J Acquire Immune Defic Syndr - 2007 Oct 1; 46(2):125-33.

13.   Merck & Company - Isentress Prescribing Information, May 2008, p. 3. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08.

14.   Merck & Company - FDA Approves Isentress (raltegravir) Tablets, First-in-Class Oral HIV-1 Integrase Inhibitor [Press Release], October 12, 2007. Available at: http://www.merck.com/newsroom/press_releases/product/2007_1012.html. Accessed 06/30/08.

15. Merck & Company - Isentress Prescribing Information, May 2008, p. 4. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08.

16.  Merck & Company - Isentress Prescribing Information, May 2008, pp. 1-2. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08.

17.  Merck & Company - Isentress Prescribing Information, May 2008, p. 2. Available     at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08.

18.  Intersci Conf Antimicrob Agents Chemother - 46th, 2006. Abstract H-1383.

19. Merck & Company - Isentress Prescribing Information, May 2008, p. 6. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08..

20. Merck & Company - Isentress Prescribing Information, May 2008, p. 1. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08

21. Merck & Company - Isentress Prescribing Information, May 2008, p. 13. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08.

22. Merck & Company - Isentress Prescribing Information, May 2008, p. 7. Available at: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf. Accessed 06/30/08.

23. Cooper D, Gatell J, Rockstroh J et al. Results of BENCHMRK-1, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. Oral abstract 105LBa.
http://www.retroconference.org/2007/Abstracts/30687.htm

24. Steigbigel R, Kumar P, Eron J et al. Results of BENCHMRK-2, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. Oral abstract 105LBa.
http://www.retroconference.org/2007/Abstracts/30688.htm

25. Grinstein B, Nguyen B-Y, Katlama C, et al. Forty-eight-week efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple class resistant virus. Program and abstracts of the 47 Interscience Conferences on Antimicrobial Agents and Chemotherapy, 17-20 September 2007, Chicago , USA . Abstract H-713.

26. Cahn P and Sued O. Raltegravir: a new antiretroviral class for salvage therapy. Lancet 2007 Apr 14; 369(9569):1235-6

27. www.futuremedicine.com, Future HIV therapy, May 2008, Vol. 2, No. 3, Pages 217-227

About Authors:

M.Sathish, M.Pharm
Address for Correspondence:
Tutor, College of Pharmacy, Madras Medical College, Chennai 600003

Mrs P.G. Sunitha, M.Pharm
Tutor, College of Pharmacy, Madras Medical College, Chennai 600003

Mrs R.Priyadharsini, M.Pharm
Tutor, College of Pharmacy, Madras Medical College, Chennai 600003