More 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. 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.

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. 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. Most experimental drugs never reach this final stage of testing.

As with older antiretrovirals, the drugs described in this page must usually be used as part of a combination of three or more medications. When a person is forced to switch drugs because they have developed a resistant strain of HIV, it is normally best to replace two or more components of the combination with drugs that work in a different way. This strategy – which depends on having a diverse range of available drugs – results in more effective and durable treatment.

Accessing investigational AIDS drugs

Clinical trials

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.

Antiretroviral drugs pipeline as of November 2009

Drug class	Recently approved	Phase III	Phase II
Entry inhibitor (CCR5)	Maraviroc (Aug. 2007)		PRO 140
Entry inhibitor (CD4)			TNX-355
Integrase inhibitor	Raltegravir (Oct. 2007)	Elvitegravir
NNRTI	Etravirine (Jan. 2008)	Rilpivirine
NRTI		Apricitabine	KP-1461 Racivir Elvucitabine

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.² This drug – marketed as Selzentry in the US and Celsentri in Europe – comes as tablets to be taken twice per day. In Europe, Maraviroc is only approved for use in patients who have exhausted other treatment options, but the FDA has approved its use in first-line therapy in the U.S.³ So far, sales have been lower than expected, largely because of the need to use tropism tests with relatively high rates of error.⁴ 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.

Vicriviroc is a similar drug that underwent Phase III trials in both treatment-experienced patients (that is, those who have already used other antiretroviral medications) and patients new to HIV therapy. An earlier trial of vicriviroc raised concern that it might increase the risk of cancer, but larger studies helped to allay such anxiety.⁵ In January 2010 Merck announced to its investors that it would not be submitting a New Drug Application (NDA) for vicriviroc in treatment-experienced patients, as the drug had not met the "primary efficacy endpoint" in two Phase III trials of this population.⁶ In July 2010 Merck halted all development of vicriviroc, following disappointing results from its study in treatment naive patients.⁷

PRO 140 is in Phase II trials and is therefore a long way from approval.⁸ 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, PRO 140 seems to have less impact on the useful functions of the CCR5 protein, which may mean it has fewer side effects.⁹ In one study, all patients who received either a 5 or 10 mg dose per kilo of bodyweight showed at least a 10-fold decrease in HIV, with 60% of the larger dose group seeing a 100-fold reduction. The biggest decrease in viral load was seen 10-12 days after administration, reaffirming the potential for dosing perhaps once every two weeks.^10 11

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.¹² 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.¹³

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.^14 15 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.¹⁶ In July 2009, Raltegravir was approved by the FDA for individuals beginning treatment for the first time, having initially been approved for treatment-experienced patients only.¹⁷ It has also received approval for treatment-naive patients in Europe.¹⁸ Raltegravir tablets are taken twice daily.

Elvitegravir is being tested in treatment-experienced patients in Phase III trials, which are expected to run until the end of 2010.¹⁹ 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 IIb trial in October 2008, the manufacturer of bevirimat, Panacos Pharmaceuticals, said it planned to proceed to Phase III trials using a newly developed tablet formulation.²⁰ However, in early 2009, Panacos Pharmaceuticals sold the rights and assets to bevirimat to US-based Myriad Genetics.²¹

In June 2010 it was reported that Myriad was halting its research programme into bevirimat in order to focus on oncology drugs.^{22 23}

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.²⁴ 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.²⁵ Taken as a tablet twice daily, etravirine is only approved for use in treatment-experienced patients. The manufacturer, Tibotec, updated its U.S. labelling in August 2009 to reflect reports of "potentially life-threatening, and fatal skin reactions" including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. In Phase 3 trials, 1.3% of participants developed severe rash, with 2% discontinuing Phase 3 trials due to rash.²⁶

Rilpivirine is undergoing Phase III trials expected to finish in August 2010.²⁷ 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.²⁸

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.²⁹ In May 2009, the manufacturers announced optimistic findings from a subsequent study, and stated they were in the process of designing further clinical studies.³⁰

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, which are now closed for data evaluation. Results are expected in the first quarter of 2010.³¹

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References

1. FDA Consumer (January-February 2000) "Experimental Treatments? Unapproved but Not Always Unavailable"
2. Pfizer (24 September 2007) "Pfizer’s Celsentri Approved in the European Union, Providing a Novel Treatment Option for Treatment-Experienced HIV Patients"
3. ViiV Healthcare (2009, 20th November, 'FDA Approves Expanded Use of Selzentry for Appropriate Patients Starting HIV Antiretroviral Therapy for the First Time'
4. Bloomberg.com (26 October 2008) "Merck, Pfizer HIV Drugs Match Bristol's First-Use Treatment"
5. Aidsmap (28 October 2008) "Vicriviroc: long-term safety concerns over cancers dispelled"
6. [PDF] Merck (2010) 'January 20, 2010 - Frequently Asked Questions and Answers - (FAQs)'
7. Aidsmap (2010, 15th July) 'Merck stops development of CCR5 inhibitor vicriviroc'
8. ClinicalTrials.gov, accessed July 2009
9. AIDSinfo (updated 16 October 2007) "PRO 140"
10. AIDSmeds.com (2009, 15th September), 'ICAAC: Single-Dose PRO 140 Reduces HIV Levels for at least 10 Days'
11. TheBody.com (2009, 22nd October), 'HIV Antiretrovirals in Development: An Update From ICAAC 2009'
12. AIDSinfo (updated 8 August 2008) "TNX-355"
13. AIDSinfo (updated 8 August 2008) "TNX-355"
14. Merck (21 December 2007) 'Isentress (raltegravir) from MSD, First Integrase Inhibitor, Approved by the European Union Commission'
15. FDA, 'Isentress Label and Approval History
16. AIDSinfo (updated 30 June 2008) "Raltegravir"
17. FDA, 'Isentress Label and Approval History
18. European Medicines Agency, 'Isentress European Public Assessment Report, product information'
19. ClinicalTrials.gov, accessed July 2009
20. Panacos (26 October 2008) "Panacos Presents Phase 2b Bevirimat Data At The 48th Annual Interscience Conference On Antimicrobial Agents And Chemotherapy"
21. Thepharmaletter (2009, 26th January) 'Myriad buys Panacos' bevirimat for $7m'
22. Aidsmap (2010, 8th June) 'Myriad halts HIV maturation inhibitor drug programme'
23. AIDSmeds (2010, 8th June) 'Myriad Genetics suspends its HIV maturation inhibitor program'
24. Tibotec (29 August 2008) "INTELENCE(TM) (Etravirine) Receives Marketing Authorisation in the European Union for HIV Combination Therapy"
25. AIDSinfo (updated 25 January 2008) "Etravirine (TMC125)"
26. Tibotec Therapeutics (2009, August), '"Dear Healthcare Professional" letter'
27. ClinicalTrials.gov, accessed July 2009
28. AIDSinfo (updated 21 June 2007) "Rilpivirine (TMC278)"
29. AIDSmeds (17 June 2008) "Experimental HIV Drug Hits Snag"
30. Koronis Pharmaceuticals (2009, 19th May) 'Koronis Pharmaceuticals' Scientific Advisory Board Confirms KP-1461 Clinical Drug Activity, HIV Ablation'
31. Avexa (2009, 2nd October), 'Avexa closes ATC's phase III trial to evaluate data'