Treatments for HIV: why do we use cocktail drugs?

An estimated 33 million people were living with HIV at the end of 20071. Someone who is infected with HIV is likely to become sick with AIDS within a few years, but if treated with antiretroviral (ARV) medication their life can be prolonged, often for a long time. ARV treatment has already dramatically cut the rate of AIDS diagnoses and deaths in Western countries where it has been provided since the mid 1990s. As of December 2007, an estimated 9.7 million of the people living with HIV in low- and middle-income countries urgently needed this life
saving ARV medication. Of these only 2.99 million – just under a third – were accessing the drugs.



ARV treatment does not cure HIV, but it can prevent the onset of AIDS for many years. This treatment consists of drugs that must be taken every day for the rest of the patient’s life. The aim of antiretroviral treatment is to keep the amount of HIV in the body at a low level. By decreasing the amount of HIV these drugs allow the immune system to recover from any damage that HIV might have caused already.



For a review on the mechanism of HIV infection view:


http://www.boehringer-ingelheim.com/hiv/art/art_videos.htm






Why do we need so many drugs?-Drug resistance



HIV is a highly variable virus which mutates very readily, which leads to a variety of HIV strains, even within the body of a single infected person. When HIV replicates it often makes slight mistakes, so each new generation of HIV differs slightly from the one before. These tiny differences in the structure of HIV are called mutations. Some of the mutations occur in the parts of HIV that are targeted by antiretroviral drugs. So although there is some HIV that continues to be attacked by the drugs, there are other strains of HIV that are less likely to be affected. This HIV is called drug resistant HIV, and it is able to replicate unaffected by the drugs.
Antiretroviral drugs slow the replication of HIV in the body. However the drugs cannot stop the replication completely, so some HIV is able to survive despite ongoing HIV treatment. Therefore if only one drug was taken, HIV would quickly become resistant to it and the drug would stop working. Taking two or more antiretrovirals at the same time vastly reduces the rate at which resistance would develop, making treatment more effective in the long term.
When someone has drug resistant HIV (commonly referred to as drug resistance), the amount of HIV in the blood rises and the risk of the person becoming ill increases. Drug resistance is one of the main reasons why antiretroviral treatment fails. If resistance develops, usually the drug regimen needs to be changed.

How many drugs are there? Our current defense for HIV and the groups of antiretroviral drugs


More than twenty antiretroviral drugs have been approved in the United States and Europe. These drugs are classified into five distinct groups based on their mode of action (watch http://www.boehringer-ingelheim.com/hiv/art/art_videos.htm) .



Entry inhibitors


CCR5 antagonists


In order to enter a human cell, HIV must first attach itself to proteins on the cell’s surface. The virus always begins by latching on to a protein called CD4. The next stage involves proteins called co-receptors, of which there are two main types: CCR5 and CXCR4. Some strains of HIV use CCR5, others use CXCR4, and some can use either. CCR5 antagonists are drugs that bind to the CCR5 co-receptor so that HIV cannot exploit it to gain entry to a cell. The main drawback of these drugs is that they don’t work against all strains of HIV.


Most people newly infected with HIV carry strains that only use the CCR5 co-receptor. As time passes the virus tends to diversify, so that around half of people in the more advanced stages of HIV infection have strains that can use CXCR4. So-called tropism tests can distinguish between the two types of virus, but these sometimes fail to detect low levels of the CXCR4-using strains.


Maraviroc became the first CCR5 antagonist to gain FDA approval in August 2007, and was approved in Europe the following month. This drug – marketed as Selzentry in the US and Celsentri in Europe – comes as tablets to be taken twice per day. Maraviroc is only approved for use in patients who have exhausted other treatment options, and so far sales have been lower than expected, largely because of the need to use tropism tests with relatively high rates of error. A more accurate tropism test was introduced in June 2008, and if maraviroc performs well in longer-term use then it may become more popular. There is even a chance that the drug could be approved for first-line treatment.


Vicriviroc is a similar drug undergoing Phase III trials in both treatment-experienced patients (that is, those who have already used other antiretroviral medications) and patients new to HIV therapy. The first studies are due to end in mid-2009. An earlier trial of vicriviroc raised concern that it might increase the risk of cancer, but larger studies have helped to allay such anxiety. It is likely that vicriviroc tablets will be suitable for once-daily dosing. PRO 140 is in Phase II trials and is therefore a long way from approval. PRO 140 contains genetically engineered antibodies, similar to the proteins the human immune system employs to fight infections. This means that PRO 140 must be injected, or else it would be destroyed in the stomach. Because it remains in the body for a long time, PRO 140 may have to be injected only once or twice per month. Compared to maraviroc and vicriviroc, PRO 140 seems to have less impact on the useful functions of the CCR5 protein, which may mean it has fewer side effects.



Anti-CD4 antibodies


TNX-355 – also known as ibalizumab – blocks HIV from entering cells by binding to the protein CD4 on the cell surface. Like PRO 140, TNX-355 contains antibodies and is injected once every two weeks (or possibly even less often). A concern is that interfering with the CD4 protein on immune cells may impair the body’s ability to fight disease, but so far no such effect has been seen in studies. As with other injected antiretrovirals, the market for TNX-355 is likely to be small; as of August 2008 it was uncertain whether the manufacturer would continue with Phase II trials.




Integrase inhibitors



Integrase is an enzyme produced by HIV. This chemical performs a crucial role in an early stage of HIV’s replication process, which takes place inside human cells. Integrase inhibitors block the action of this enzyme, thus preventing the virus from making new copies of itself. These drugs are effective against HIV that has become resistant to other antiretroviral classes.
Raltegravir is the only approved integrase inhibitor, having been cleared by the FDA in October 2007 and in Europe two months later.11 Sold under the brand name Isentress, it is notable for the speed with which it suppresses HIV. So far no serious side effects have been observed. The current approval applies to treatment-experienced patients only, but the manufacturer hopes the drug may yet become an option for people starting treatment for the first time.


Elvitegravir is being tested in treatment-experienced patients in Phase III trials, which are expected to run until the end of 2010. This integrase inhibitor (in common with most protease inhibitors) requires a small dose of the drug ritonavir to boost its effectiveness. Such a combination of tablets may be suitable for once-daily dosing.



Maturation inhibitors



Bevirimat is a maturation inhibitor – a drug designed to halt the development of immature HIV particles after they have emerged from human cells. After presenting the results of a Phase II trial in October 2008, the manufacturer of bevirimat said it plans to proceed to Phase III trials using a newly developed tablet formulation. The market for bevirimat may be limited because studies have found that around a third of people infected with HIV carry strains that are partially resistant to this drug.




NNRTIs


NNRTIs (non-nucleoside reverse transcriptase inhibitors) are an older class of antiretroviral drug – the first was approved in 1996. Nevertheless, until recently just three members of this group were available: efavirenz and nevirapine (both widely used in first-line treatment) and delavirdine (only rarely used). Because these three drugs work in a very similar way, once HIV develops resistance to one of them then the others are often ineffective as well. Newer NNRTIs are designed to work differently so as to avoid this problem of cross-resistance.


Etravirine – sold as Intelence – gained FDA approval in January 2008 and was approved in Europe the following August. This NNRTI is active against some strains of HIV that are resistant to efavirenz or nevirapine. However, if the virus has developed a very strong form of resistance to the other drugs then etravirine might not work. Taken as a tablet twice daily, etravirine is only approved for use in treatment-experienced patients.


Rilpivirine is undergoing Phase III trials expected to finish in August 2010.17 It is a once-daily pill that could emerge as a preferred option for people starting treatment for the first time. Rilpirivine appears to be as effective as the current favourite NNRTI, efavirenz, but with fewer side effects. Unlike efavirenz, it does not appear to cause central nervous system effects such as anxiety, sleep disturbance and depression.




NRTIs


NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) were the first medicines to be approved for the treatment of HIV. Eight of these drugs are currently available. Typically an antiretroviral treatment combination consists of two NRTIs and one drug from another class.
KP-1461 takes a unique approach to fighting HIV called Viral Decay Acceleration. The idea is to increase the rate at which HIV mutates when it replicates, so that the virus soon becomes too deformed to survive. KP-1461 performs this task by inserting faulty elements into HIV’s genetic code. Because it targets all HIV proteins rather than a single protein, its developers hope that KP-1461 may be less vulnerable to drug resistance. Enthusiasm for this drug was dampened, however, when a Phase II trial was suspended in June 2008. Most patients in this trial showed no reduction in levels of HIV, contradicting the results of previous research. It is unclear whether the trial will be restarted.


Apricitabine, Elvucitabine and Racivir are more conventional NRTIs that are undergoing clinical trials. Apricitabine and racivir are similar in structure to 3TC (lamivudine) and FTC (emtricitabine), which are widely used in first-line treatment. Studies suggest that all three of these experimental drugs can control HIV that is resistant to some other NRTIs, so they may provide useful options for second-line treatment. Apricitabine is the only one of the three to have entered Phase III trials.




What does combination therapy usually consist of?


The most common drug combination given to those beginning treatment consists of two NRTIs combined with either an NNRTI or a "boosted" protease inhibitor. Ritonavir (in small doses) is most commonly used as the booster; it enhances the effects of other protease inhibitors so they can be given in lower doses. An example of a common antiretroviral combination is the two NRTIs zidovudine and lamivudine, combined with the NNRTI efavirenz. Some antiretroviral drugs have been combined into one pill, which is known as a fixed dose combination. This reduces the number of pills to be taken each day. The choice of drugs to take can depend on a number of factors, including the availability and price of drugs, the number of pills, the side effects of the drugs, the laboratory monitoring requirements and whether there are co-blister packs or fixed dose combinations available.




Hope for the future: the new line of defense against HIV


Although more than twenty antiretroviral drugs have been approved for treating HIV there is still a great demand for additional options. New AIDS drugs are most urgently needed for people who have had to abandon existing products due to drug resistance or side effects. In addition new antiretrovirals can bring benefits such as fewer side effects, less frequent dosing and lower risk of drug resistance. New drugs have been recently approved by the FDA or are currently in the process of being approved. We are now going to explore how these new drugs work.

References:



1. www.foxnews.com
2. http://www.avert.org/
3. Pfizer "Pfizer’s Celsentri Approved in the European Union, Providing a Novel Treatment Option for Treatment-Experienced HIV Patients"
4. Bloomberg.com "Merck, Pfizer HIV Drugs Match Bristol's First-Use Treatment"
5. Monogram Biosciences "Data Reported at ICAAC Indicates Selzentry(TM) Phase III Treatment-Naive Trial Shows Increased Efficacy When Used With Enhanced Trofile(TM) Assay"
5. ClinicalTrials.gov
6. Aidsmap "Vicriviroc: long-term safety concerns over cancers dispelled"
7. ClinicalTrials.gov
8. AIDSinfo "PRO 140"
9. AIDSinfo "TNX-355"
10. AIDSinfo "TNX-355"
11. Merck "Isentress (raltegravir) from MSD, First Integrase Inhibitor, Approved by the European Union Commission"
12. AIDSinfo "Raltegravir"
13. ClinicalTrials.gov
14. Panacos "Panacos Presents Phase 2b Bevirimat Data At The 48th Annual Interscience Conference On Antimicrobial Agents And Chemotherapy"
15. Tibotec "INTELENCE(TM) (Etravirine) Receives Marketing Authorisation in the European Union for HIV Combination Therapy"
16. AIDSinfo "Etravirine (TMC125)"
ClinicalTrials.gov
17. AIDSinfo "Rilpivirine (TMC278)"
18. AIDSmeds "Experimental HIV Drug Hits Snag"