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HIV Drugs Development

Antiretroviral drugsMore than twenty antiretroviral drugs have been approved for treating HIV, yet there is still a great demand for additional options. New HIV drugs are most urgently needed for people who have had to abandon existing products due to drug resistance or side effects, and may be forced to switch drugs as a result. For this group, access to a new medication can mean the difference between life and death. More generally, new antiretrovirals can bring benefits such as fewer side effects, less frequent dosing and a lower risk of drug resistance.

The antiretroviral drug pipeline consists of a variety of pipeline compounds in the main five drug classes, as well as 'booster' drugs, fixed dose combinations (FDCs) and a potential new type of drug, the 'maturation inhibitor'. This page looks at antiretroviral drugs that have recently been approved by the FDA (Food and Drug Administration) for use in the USA, or that are undergoing Phase II or Phase III trials. Some antiretroviral drugs that showed early promise in clinical trials but have been halted or discontinued are also mentioned.

Drugs must undergo three stages of testing for safety and effectiveness before they may gain approval. Phase III trials are by far the largest and most expensive, typically lasting more than a year and having hundreds or even thousands of participants. As a result, most experimental drugs never reach this final stage of testing.

Accessing investigational AIDS drugs

Clinical trials

“New drugs must undergo clinical trials to test safety and effectiveness before being approved for sale.”

New drugs must undergo clinical trials to test safety and effectiveness before being approved for sale. Taking part in a trial is one way to gain access to a drug that is not yet generally available.

Patients interested in clinical trials should begin by talking to their doctors. However, not all doctors will be aware of all the options, so it is also worthwhile doing research. Many websites, such as clinicaltrials.gov in the USA, carry information about trials that are seeking participants.

Not everyone who wants to take part in a trial is able to do so. Eligibility may depend on previous treatment, health, age or gender, for example. The number of participants is usually limited, and most trials take place at a few clinics only.

In addition, not everyone who takes part in a trial will receive the drug being studied. Usually a new treatment is tested against an existing alternative, with patients randomly assigned to receive one or the other.

It is important to understand that trials carry risks as well as possible benefits. It may turn out that the new drug is less effective than the old one. There is also a chance that the new drug may have serious side effects not detected in earlier studies. Participating in a trial may be time consuming and inconvenient.

Patients should find out as much as they can about a trial before enrolling, to assess whether the benefits are likely to outweigh the risks.

Expanded access

Drugs undergoing clinical trials are known as investigational treatments. Patients who can’t take part in trials may be able to access an investigational treatment through an expanded access programme or compassionate release scheme. In America, for example, the Food and Drug Administration (FDA) allows three main options for people living with HIV:

  • Treatment IND
  • Single-patient IND (or compassionate use IND)
  • Emergency use IND

A treatment IND (Investigational New Drug application) allows the makers of a new drug to run a programme supplying it to patients in need, provided the drug has already shown promise and proven safety, and no comparable or satisfactory alternative is available. Those interested in accessing a drug under a treatment IND should contact the organisers of the programme.

Not every investigational drug is available under a treatment IND. In this case a doctor may apply for a single-patient IND (also known as a compassionate use IND) to help a particular individual. For this to work the manufacturer must be willing to supply the drug and create a way to monitor the patient while on treatment.

If a patient’s life is in immediate danger then a doctor may seek an emergency IND, which allows a drug to be supplied more quickly, before completion of the formal approval process.

Similar mechanisms exist in many other countries with different terminology. In the UK, a process called named-patient prescribing is roughly equivalent to a single patient IND.

The FDA says that the single-patient IND “virtually ensures that any patient can get access to any investigational new drug… FDA only denies access when there is evidence that the risk of using the experimental drug clearly outweighs any potential benefit to the patient.” 1

In reality, however, accessing an investigational treatment may not be straightforward. A manufacturer may not want to supply a drug because of the cost and logistical challenges. Some doctors may be reluctant to allow use of an unproven medication; patients may have to seek out information to support their case or, as a last resort, find a more willing doctor.

News about drug development and expanded access programmes can be found on many websites, message boards and newsletters published by HIV treatment activists.

Phase III antiretroviral drug trials as of August 2013

CompoundRecently approvedPhase III
Entry inhibitor (CCR5)Maraviroc - Aug. 2007 
Integrase inhibitorRaltegravir - Oct. 2007 
Integrase inhibitor Elvitegravir
Integrase inhibitorDolutegravir - Aug. 2013 
Pharmacokinetic booster Cobicistat
NNRTIEtravirine - Jan. 2008 
NNRTIRilpivirine - May 2011 
NRTI Apricitabine
NtRI Tenofovir alafenamide (tenofovir prodrug)
Fixed Dose Combination (FDC)Rilpivirine + FTC + TDF (Complera) - Aug. 2011 
Fixed Dose Combination (FDC)Elvitegravir + Cobicistat + FTC + TDF (Stribild) – Aug. 2012 
Fixed Dose Combination (FDC)Quad (boosted integrase inhibitor + Truvada) - Submitted for approval 

There were also eight Phase II trials as of June 2013. 2 3 4

Drug classes

The antiretroviral drugs in Phase II and Phase III trials fall into four of the five antiretroviral drug classes; fusion/entry inhibitors, integrase inhibitors, NRTIs and NNRTIs. Protease inhibitors are the other type of antiretroviral drug but there are currently no experimental protease inhibitors in Phase II or Phase III clinical trials. Research is also underway into a type of drug which could form a potential new drug class, the maturation inhibitor.

The HIV replication cycle

Fusion or Entry inhibitors

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 a type of entry inhibitor 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.

Integrase inhibitors

Tables of Isentress (raltegravir), an integrase inhibitor used for HIV treatmentIntegrase 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.

Maturation inhibitors

Maturation inhibitors are a potential new drug class which seeks to halt the development of immature HIV particles after they have emerged from human cells.

NNRTIs

NNRTIs (non-nucleoside reverse transcriptase inhibitors) are an older class of antiretroviral drug – the first was approved in 1996. NNRTIs stop HIV replicating within cells by interfering with HIV's reverse transcriptase protein which it needs to make new copies of itself. 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.

NRTIs

NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) were the first medicines to be approved for the treatment of HIV. NRTIs stop HIV from replicating within cells by inhibiting the reverse transcriptase protein. Eight of these drugs are currently available. Typically an antiretroviral treatment combination consists of two NRTIs and one drug from another class.

 

References

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