Highly Active Anti Retroviral Therapy Combination Biology Essay


There are six main categories of antiretroviral drugs categorised so far. And these are chemokine competitors coreceptor two subcategories: CCR5, and CXCR4 antagonist competitor and integrase inhibitor

Fusion inhibitors prevent HIV from entering target cells. Drugs of this class bind to the HIV envelope protein gp41, which is involved in viral entry. By blocking the interactions between regions of the gp41 molecule, fusion inhibitors interfere with the conformational change (folding) of the envelope molecule required for fusion with the target cell membrane.

NNRTIs also inhibit viral DNA synthesis, but instead act as a false nucleotide, NNRTIs bind the transcription in a manner that inhibits the activity of the enzyme reverse

NRTIs function by inhibition of DNA synthesis by reverse transcriptase (an enzyme that copies the viral RNA into DNA) in infected cells. Nucleoside analogues have a structure similar to natural building blocks of DNA: adenosine and guanosine nucleoside thymidine and cytidine. Triphosphorylated nucleoside analogs are within the cell, and some subject to change (didanosine, for example, becomes the active moiety, 2 ', 3'-dideoxyadenosine-5'-triphosphate). Resemble nucleotide monophosphorylated nucleosides, and therefore require only two additional phosphorylations to become active inhibitors of DNA synthesis. Reverse transcriptase does not distinguish the phosphorylated NRTIs from their natural counterparts, and attempts to use drugs in the synthesis of viral DNA. When an NRTI is incorporated into a DNA strand is synthesized, the addition of nucleotides is prevented, and a complete copy of the viral DNA does not occur.

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Chemokine coreceptor antagonists also prevent the entry of HIV into target cells. They bind to coreceptors (either CCR5 or CXCR4) on the surface of CD4 cells. Thus, the block is a necessary step in viral entry. Drugs, which in contrast to other categories of work on viral enzymes, coreceptor liabilities associated with human proteins. For example: Maraviroc

Protease Inhibitors (PIS) is a class of drugs used to treat or prevent infection by viruses, including HIV and hepatitis C inhibitors prevent protease viral replication by inhibiting the activity of HIV- a protease, an enzyme used by viruses to cleave nascent proteins for final assembly of new Virons. The Viral particles still produced (when the protease is inhibited) are not effective at infecting new cells.

Integrase inhibitor binds integrase (an enzyme in the virus) and prevents the integration of the reverse-transcribed HIV DNA into the chromosomes of host cells. For Example: Raltegravir (MK-0518) and Elvitegravir (GS-9137)

AptivusTM (Tipranavir)

Initially AptivusTM was developed by Pharmacia & Upjohn Company LLC and was finally acquired by Boehringer Ingelheim Pharmaceuticals Inc. (An American Company.

In America, it was approved in June 2005 by FDA for use in combination with ritonavir in adults with HIV infection. In 2008, it received approval for children age 2 years and older. It is intended to be used as part of combination therapy in patients who have HIV strains that are resistant to multiple other protease inhibitors and have an ongoing viral replication while taking antiretroviral therapy. It was also the first non-protease inhibitor approved in Europe in July 2005.

FDA approval was based on 2 Phase III studies in patients with extensive prior treatment with protease inhibitors, nucleoside analogues, and nonnucleoside reverse transcriptase inhibitors. All patients had HIV-1 with evidence of resistance to protease inhibitors.


Figure Tipranavir (TPV) is a new class of protease inhibitor (PIs) with a non-peptide activity against wild type virus and also mutants resistant to present PIs [S. Rusconi, C.S. La Seta, et al]; Antimicrob Agents Chemother. 2000]. TPV has been developed from coumarin and sulfonamide models, and thus differs significantly from the structure of all the PIs peptido-mimetic developed at this time. TPVis principally metabolized by, and is also an inducer of cytochrome P450 3A4 (CYP3A4) enzyme. TPV is a P-glycoprotein (P-gp) substrate, even a low P-gp inhibitor, and appears to be a potent inducer of P-gp, producing a net effect of P-gp air intake on TPV / r steady state. Consequently, TPV / r model a bit more complex interactions than other PIs.Tipranavir.JPG

Therefore, the combination of amprenavir (APV), lopinavir (LPV) or saquinavir (SQV) with TPV / r is not currently indicated as a clinically significant decrease of exposure co-administered drugs.

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Ritonavir, with trade name Norvir (manufactured by Abbott Laboratories) is an antiretroviral drug in the class of protease inhibitors used to treat HIV infection and AIDS.

Ritonavir is often prescribed for HAART, and not for its antiviral action, but because it inhibits the enzyme metabolizes same host other protease inhibitors. This inhibition leads to higher plasma concentrations of these substances, so the clinician to reduce their dose and frequency and improve their clinical efficacy.

HAART: combination therapy:

HAART (Highly Active Anti-Retroviral Therapy) combines three or more medications at least two different classes to remove the process of virus replication in at least two different ways. Using this method, the replication process is slower and the speed with which resistance may develop, are much lower, because HIV have more difficulty in overcoming this combined attack.

The importance of every dose: For HAART to be effective, it is important to take each dose of medication as prescribed. Poor adherence to HAART has been shown that following treatment failure and more rapid progression of the disease. If there is an error in the dose ingested virus can copy faster and the risk of developing resistance increases.

So, HAART is not a cure for HIV, but it is a strong and long-lasting therapy to prevent a weakening of the immune system and the development of opportunistic infections.

Dosage and Administration:

The approved dose of TPV is 500 mg in association with 200 mg of ritonavir (TPV/r) taken twice daily as part of combination antiretroviral therapy for HIV-1 in heavily pre-treated patients having HIV-1 strains resistant to multiple PIs.

Dosing of Tipranavir + Ritonavir


Tipranavir 500 mg BID + ritonavir 200 mg BID


(2-18 years)

Tipranavir 14 mg/kg BID + ritonavir 6 mg/kg BID (or tipranavir 375 mg/m2 BID + ritonavir 150 mg/m2 BID); not to exceed tipranavir 500 mg BID + ritonavir 200 mg BID

Clinical Studies

The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST)

(a) RESIST 1

Efficacy of the Protease Inhibitors Tipranavir plus Ritonavir in treatment-experienced patients: 24-Week Analysis from the RESIST-1 Trial

For infected patients improved treatment was needed with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitorâ€"resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1â€"infected patients.


TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.

The side-effects were slightly more common in TPV/r patients and included vomiting, diarrhea and nausea. Also higher level of cholesterol and alanine and aspartate aminotransferase was found (can be possible due to higher total daily dose). Though, there was no significant increase in glucose level.

(b) RESIST 2.

The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-2) trial is an ongoing, open-label, phase III trial comparing ritonavir-boosted tipranavir (TPV/r) plus an optimized background regimen with an individually optimized, ritonavir-boosted protease inhibitor in treatment-experienced, HIV-1â€"infected patients.

Each patient also was given an optimized background regimen, which could include enfuvirtide. At 24 and 48 weeks, the tipranavir group had higher rates of virologic response (defined as ≥1 log10 decrease in HIV RNA) and viral suppression to <400 copies/mL and to <50 copies/mL than did the comparator group; these differences were statistically significant.

Important parameters

Regular monitoring of CD4+ cell count and the viral load are important factors in treatment of HIV. Only by monitoring symptoms and treatment effects can clinicians advise on the best time to start treatment and the best treatment options to meet specific individual life style and health needs.

Viral load: The viral load is the amount of HIV in the blood. Regular monitoring of the amount of HIV present in the blood (viral load) is an important factor in the treatment of HIV. Monitoring viral load informs the treatment path, i.e. levels of viral load determine when to start antiretroviral drug therapy or how well a certain therapy is working. The viral load measurement can help to estimate how rapidly the CD4+ cell count is likely to drop in the future. Comparing the monitored values with a "typical" clinical course of infection makes it easier to pinpoint the right time for antiretroviral treatment to begin. Additionally, monitoring values during treatment supports treatment decisions.

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CD4+ cell count: The viral load is directly correlated to the number of CD4+ cells. Since, a high viral load leads to a decreasing CD4+ cell count and a weakened immune system, regular monitoring is important to react in time. CD4+ count acts as a marker for the determining the strength of immune system, choosing a therapy and evaluating different treatment options for HIV-infected people. To reduce the viral load and thus increase the CD4+ cell count, antiretroviral drug treatment is necessary.