HIV belongs to the special class of viruses called retroviruses. Within this class, HIV is placed in the subgroup of lentiviruses. Most of the viruses contain DNA as genetic material but in the case of Retroviruses are containing RNA which is the exception. RNA has a very similar structure to DNA.

HIV’s replication process is a bit more complicated than that of most other viruses. HIV has just nine genes. Three of the HIV genes, called gag, pol and env, contain information needed to make structural protein for virus particles. The other six genes, known as tat, rev, nef, vif, vpr and vpu, code for proteins that control the ability of HIV to infect the cell, produce new copies of virus, or causes disease. At either end of each strand of RNA is sequence called the long terminal repeat, which helps to control HIV replication.²

Here we introduce briefly various current therapies used in the treatment of AIDS like Highly active antiretroviral therapy, Salvage therapy and new treatment strategies.

Also here we introduce drugs under clinical trials like BT378/r and HIV vaccine and our main focus is to high light an integrase inhibitor – Raltegravir.

Discussion:

AIDS is a disease caused by the retrovirus Human Immunodeficiency Virus (HIV) and is characterised by the profound immunosuppression that leads to the opportunistic infections, secondary neoplasm and neurologic manifestations.

Here, we focus on the treatment and prevention of HIV, various current therapies which are been given and also here we highlight the drug and vaccine under clinical trials. The main aim of these discussion is to understand Intregrase Inhibitor –Raltegravir Which is a new approach to antiretroviral therapy, here we try to understand the basic mechanism by which it act, there dynamics and kinetics protocol together with its various pharmacological parameters.

When HIV was first identified in the early 1980s, there were few drugs to treat the virus and the opportunistic infections associated with it. Since then, a number of medications have been developed to treat both HIV/AIDS and opportunistic infections. For many people, including children, these treatments have extended and improved their quality of life. Scientists at the National Institutes of Health estimate that since 1989, anti-retroviral medications have provided HIV-positive Americans with years of extended life. But none of these drugs can cure HIV/AIDS, many have side effects that can be severe, and most are expensive. What's more, after 20 years on AIDS drugs, some people develop resistance to the drugs and no longer respond to treatment. Newer drugs are being researched and created to help this group of people.

According to current guidelines, treatment should focus on achieving the maximum suppression of symptoms for as long as possible. This aggressive approach is known as highly active anti-retroviral therapy (HAART). The aim of HAART is to reduce the amount of virus in your blood to very low or even non detectable levels, although this doesn't mean the virus is gone. This is usually accomplished with a combination of three or more drugs.³

i) NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI)

ii) Reverse transcriptase converts viral RNA into proviral DNA before its incorporation into the host cell chromosome. Because agents in this class act at an early and initial step in HIV replication, they prevent acute infections of susceptible cells but have little effect on cells already infected with HIV. All drugs of this class are substrates of reverse transcriptase. To become active, these drugs first must be phosohorylated by host cell enzymes in the cytoplasm. Since NRTI lack a 3’ hydroxyl group, incorporation into DNA terminates chain elongation. Example of this class is Zidovudine.^4,5

iii) NONNUCLEOSIDE REVERSE RANSCRIPTASE INHIBITORS (NNRTI)

The NNRTI’s are a class of chemically distinct synthetic compounds that block reverse transcriptase activity by binding adjacent to the enzyme’s active site inducing conformational changes in this site. The agents share only a common mechanism of action but also toxicities and resistance profiles. Unlike nucleoside analogs, NNRTIs do not undergo phosphorylation . They are active against only HIV-1. All compounds in this class are metabolized by the CYP450 system and thus are prone to drug interactions. Example of this class is Nevirapine.^4,5

iv) PROTEASE INHIBITORS:

HIV proteases cleave the viral polyprotien into the active enzymes and structural proteins. Saqunavir binds to the active site of HIV protease, preventing polypeptide processing and subsequent viral maturation. The most common mutation associated with Saquinavir resistance is at protease codon 90 followed by codon 48. With prolonged administration, additional mutations at positions 36, 46, 82 and 84 occur and are associated with cross resistance to other protease inhibitors.^4,5

CURRENT THERAPY USED IN THE TREATMENT OF AIDS:

i) HAART (Highly Active Antiretroviral Therapy):^6-8

For antiretroviral treatment to be effective for a long time, it has been found that you need to take more than one antiretroviral drug at a time. This is what is called as combination therapy. The term HAART is used to describe a combination of more than three or more anti HIV drugs. When HIV replicates it makes mistakes, this means that within any infected person there are many different kinds of strains of virus. Occasionally, a new strain is produced that happens to be resistant to the effects of an antiretroviral drug. If the person is not taking any of the other type of drug then the resistant strain is able to replicate quickly and the benefits of the treatment are lost. Taking two or more antiretroviral at the same time vastly reduces the rate at which resistance develops. A DOT-HAART regimen taken once daily would make possible a high level of patient adherence to drug treatment as has previously been seen in well-run, DOT-based tuberculosis treatment programs in poor countries.

Treatment combinations should comprise two NRTI’s usually referred as the backbone of the regimen, plus a third agent. The drug regimen need to be individualized in order to maximize adherence (poor adherence can lead to development of resistance) and so should be given to potentate toxicities, drug interactions, potency and tolerability the current available combination therapy available are:-

a. 2NRTI‘s + PI

b. 2NRTI’s +2PI’s

c. 2NRTI’s + NNRTI

d. 3NRTI’s

ii) SALVAGE THERAPY:⁶

Salvage therapy is the term given to drug therapy after one then one previous failure. It is also called as third line therapy. Patients by this stage have usually had multiple exposures to all three classes of antiretroviral drugs. Resistance testing is strongly recommended when attempting to construct a salvage regimen. The studies on salvage therapy to date have been to short duration with little follow up data. It is likely that this therapy will be more successful in patients who have lower viral load. Improved outcome is more likely with the use of drugs to which the patient has not been exposed or to which resistance is unlikely. In each case, it is important to construct a fully suppressive regimen from the remaining drugs. Sometimes it may be more beneficial for the patient to wait for new therapies to become available if being off therapy does not pose an intermediate risk.

RECENT ADVANCES IN THE DISCOVERY AND DEVELOPMENT OF ANTI-HIV AGENTS

DRUGS UNDER CLINICAL TRIAL

Ø BT378/r:⁹

BT378/r is a new protease inhibitor in clinical trials at present. The drug is manufactured as a dual capsule containing a small dose of (100 mg) Ritonavir. The rationale for this is that much higher levels of BT378 are obtained in the body as a result of metabolic inhibition by Ritonavir (inhibitor of CYP450). The toxicity profile of this new drug appears to be favourable and it is thought that it may be useful in patients who have previously failed on a PI containing regimen.

Ø HIV Vaccine:

The first large AIDS vaccine trials found that a recombinantglycoprotein 120 vaccine (based on the viral envelope) thatinduced neutralizing antibodies did not protect against HIVinfection.^10,11

To evaluate the safety of the vaccine and its ability to generate immune response in HIV-uninfected, healthy volunteers. This international multi-centric trial is being conducted by the National AIDS Research Institute, Pune, under the joint auspices of the National AIDS Control Organization (Ministry of Health and Family Welfare, Government of India), the Indian Council of Medical Research (ICMR) and sponsored by the International AIDS Vaccine Initiative (IAVI).

The vaccine being tested is called tgAAC09. The vaccine does not contain HIV virus. Therefore the volunteers cannot get infected with HIV from this vaccine. This is a preventive vaccine intended for people who are not infected with HIV and not for persons living with HIV. It is not a drug for AIDS. This particular vaccine has been tested in animals prior to this trial. Data from animal and pre-clinical studies indicate that the vaccine was safe and was well tolerated, allowing testing in human beings. This Phase-I trial is currently ongoing in two European countries, Belgium and Germany where fifty volunteers have already received this vaccine in whom it was found to be safe.

This vaccine will be tested for the first time in human beings in India at NARI in Pune. Three groups of volunteers will receive three different doses of vaccine (low, medium and high) and the volunteer may be in any one of these groups. The vaccine will be given intramuscularly in the upper arm. Signing informed consent for screening, tests and evaluation, Medical history and physical examination and Blood tests including HIV test, Urine examination.

Possible risks and discomforts as after any injection, participants may experience some mild or moderate reaction at the injection site (Editioness, swelling, pain and tenderness, and in very rare cases, the formation of a scab and skin discoloration), reactions that will only be temporary. Participants may also experience mild fever, chills, headache, nausea, fatigue, vomiting, malaise, mild muscular pain and joint pain. Participants may not experience any of them.

Like any new drug or vaccine, there is a possibility of a totally unexpected side effect, although previous testing with other vaccines in other countries indicates that this vaccine is quite safe.

This clinical trial is not designed to study whether tgAAC09 can protect against HIV infection (efficacy). Therefore participants must avoid any behaviour that may put them at risk of contracting HIV. Participants should not consider themselves protected from HIV after receiving the injection. It is not known what effect/s the test vaccine might have on an unborn child. This is a Phase-I trial of a newly developed experimental AIDS vaccine.

The MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. Vaccine-induced immunity and its potential contributions to infection risk.

LATEST ADVANCES IN THE TREATMENT OF AIDS:

RALTEGRAVIR:

Raltegravir (isentress) is an antiretroviral drug 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.^[12]

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.¹³

Raltegravir structure (Fig-1)

Fig:1 The empirical formula is C₂₀H₂₀FKN₆O_5.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.¹³

MECHANISM OF ACTION OF RALTEGRAVIR:^14,15

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.^16,17

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 than 50 copies per millitre sooner than 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.¹⁸ Research into Raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing.¹⁹

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.²⁰

PHARMACOKINETICS OF RALTEGRAVIR:

Absorption:²¹

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. 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%.

Distribution²¹

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

Metabolism and Excretion^13\

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.

Plasma, urine, and fecal samples were collected at specified intervals up to 240 h post dose, and the samples were analyzed for total radioactivity, parent compound, and metabolites. Radioactivity was eliminated in substantial amounts in both urine (32%) and feces (51%). The elimination of radioactivity was rapid, since the majority of the recovered dose was attributable to samples collected through 24 h. In extracts of urine, two components were detected and were identified as Raltegravir and the glucuronide of Raltegravir (M2), and each accounted for 9% and 23%of the dose recovered in urine, respectively (PDF 1) (fig-2).

Fig 2: Elimination rate of Raltegravir,

Adverse effects:

In Phase II studies, the most commonly reported treatment-related adverse effects were diarrhoea, nausea, fatigue, headache, and itching. Other reported adverse effects included constipation, flatulence, and sweating. Overall, Raltegravir was well tolerated, and its adverse effects were comparable e to those in the placebo group.^21,22In 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.²³

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 diarrhoea, nausea, headache, and pyrexia.^24,25Additionally, Grade 2 to 4 creatine kinase laboratory abnormalities were observed in clinical trial participants treated with Raltegravir.²⁶

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.²⁷

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.¹³

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.²⁵ 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.²⁸

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.²⁹ 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 tipranavir³⁰Drugs 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.³¹

Effect of Raltegravir on the Pharmacokinetics of Other Agents:¹³

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 CYP3A4in 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:¹³

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) 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.

Co-administration of ISENTRESS with other drugs that inhibit UGT1A1 may increase plasma levels of Raltegravir.

Warnings and precautions of Raltegravir:¹³

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.

Fertility And Pregnancy:²⁰

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.

DOSING INFORMATION:

Mode of Delivery: Oral:²⁵

Dosage Form:

Tablets containing Raltegravir 400 mg.²⁶

The recommended dose of Raltegravir in treatment-experienced HIV-infected adults is one 400-mg tablet twice daily.^[31] No dosage adjustment is necessary in patients with mild to moderate hepatic or severe renal impairment.³²

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.³³

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).^[34]

RESISTANCE TO INTEGRASE INHIBITORS:^32,33

Integrase inhibitors are the most recently approved family of antiretroviral agents for the treatment of HIV infection. As with other antiretroviral agents, under pharmacological pressure, the virus selects resistance mutations if viral suppression is incomplete. Mutations are selected in the integrase gene, specifically in positions proximal to the catalytic canter. Because clinical experience with these drugs is scarce, information on resistance is limited. Virologic failure with Raltegravir is associated with selection of primary mutations such as N155H (40%) and distinct changes in position Q148 (28%). Less frequently, Y143R (6.6%) and E92Q are selected. The most frequently observed mutations in failure with Elvitegravir are E92Q, E138K, Q148R/K/H and N155H, and less frequently S147G and T66A/I/K. The most common resistance pattern seems to be E138K + E147G + Q148R. There is a high grade of cross resistance between Raltegravir and Elvitegravir, making sequencing between these two drugs impossible.

CLINICAL STUDIES:

New Antiretroviral:^34,50

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.

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)³⁵ 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 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.

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.³⁶

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.^[16]

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.^14,36

CONCLUSION:

Human immunodeficiency virus type 1 (HIV-1) integrase is one of three virally encoded enzymes essential for replication and, therefore, rational choice as a drug target for the treatment of HIV-1 infected individual. In 2007, raltegravir became the first integrase inhibitor approved for use in the treatment of HIV-1 patients, more than a decade since the approval of the first protease inhibitor and two decades since the approval of the first reverse trancriptase inhibitor. The slow progress toward a clinically effective HIV-1 integrase inhibitor can at least in part be attributed to a poor structural understanding of this key viral protein.

An integrase inhibitor which is active against retrovirus, found to be more beneficial compare to other currently use drugs, also it has been found to be effective again resistive subject and increase their like livelihood.

Here we described the development of a restrained molecular dynamics, kinetics protocol and pharmacological aspects that produce a more accurate model of the active site of this drug target.

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Received on 19.02.2011

Accepted on 13.03.2011

Research J. Pharmacology and Pharmacodynamics. 3(2): March –April, 2011, 58-66