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New Antiretroviral Drugs

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, 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.

back to top 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.

back to top Phase III antiretroviral drug trials as of August 2011

Compound
 Recently approved Phase III
Entry inhibitor (CCR5) Maraviroc - Aug. 2007
Entry inhibitor (CD4)
Integrase inhibitor Raltegravir - Oct. 2007
Integrase inhibitor   Elvitegravir
NNRTI Etravirine - Jan. 2008

Rilpivirine - May 2011
NRTI Apricitabine
Fixed Dose Combination (FDC) Rilpivirine + FTC + TDF (Complera) - Aug. 2011
Fixed Dose Combination (FDC) Elvitegravir + Cobicistat + FTC + TDF (Stribild) – Aug. 2012

There were also around nine Phase II trials as of August 2011.2 3 They include the trials for entry inhibitors PRO 140 and TNX-355 and the NRTIs KP-1461, Racivir and Elvucitabine which are discussed below. 

back to top 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.

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.

HIV Replication Cycle HIV Replication Cycle

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

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.

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.

back to top Entry inhibitors

Recently approved

Maraviroc became the first CCR5 antagonist to gain FDA approval in August 2007, and was approved in Europe the following month.4 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.5 So far, sales have been lower than expected, largely because of the need to use tropism tests with relatively high rates of error.6 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.

Discontinued trials

Vicriviroc is a similar drug to Maraviroc 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.7 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.8 In July 2010 Merck halted all development of vicriviroc, following disappointing results from its study in treatment-naive patients.9

Phase II trials

PRO 140 is in Phase II trials and is therefore a long way from approval.10 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.11 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.12 13

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.14 As with other injected antiretrovirals, the market for TNX-355 is likely to be small. In 2007, the license for the drug was sold to TaiMed Biologics which is undertaking a Phase II trial for the drug.15

BMS-663068 is an entry inhibitor which targets the very first step of HIV binding to cells. Most entry inhibitors work by interfering with the second and third steps of HIV entry - when HIV binds to the co-receptor and then fuses with the membrane of the cell. BMS-663068 binds to the glycoprotein gp120 on HIV-1 which then stops HIV from binding to a cell's co-receptor in the first place. In clinical trials BMS-6603068 was shown to lead to declines in HIV viral loads as well as an increases in CD4 count.16       

Cenicriviroc is a CCR5 anatagonist which has so far been shown to 'significantly decrease' viral load among Phase II trial participants.17 Cenicriviroc also acts an anti-inflammatory. Side effects associated with Cenicriviroc in trials so far include fatigue, diarrhoea and nausea.18

back to top Integrase inhibitors

Recently approved

Tablets of Isentress (raltegravir), an integrase inhibitor used in HIV treatment Tablets of Isentress (raltegravir), an integrase inhibitor used in HIV treatment

Raltegravir is the only approved integrase inhibitor, having been cleared by the FDA in October 2007 and in Europe two months later.19 20 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.21 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.22 It has also received approval for treatment-naive patients in Europe.23 Raltegravir tablets are taken twice daily.

Phase II trials

Dolutegravir is being studied as an integrase inhibitor option for treatment experienced patients who are resistant to integrase inhibitors raltegravir or elvitegravir. According to trials so far, dolutegravir is well tolerated at a daily dose of 50 mg which is what has been required to be efficient against raltegravir-resistant HIV.24

Phase III trials

Elvitegravir is being tested in treatment-experienced patients in Phase III trials and an application has been made to the FDA for its approval.25 26 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. Elvitegravir has been approved for use as part of a 'quad therapy' that combines four drugs into a single pill. This fixed dose combination has the brand name ‘Stribild’.27

back to top Maturation inhibitors

Discontinued trials

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.28 However, in early 2009, Panacos Pharmaceuticals sold the rights and assets to bevirimat to US-based Myriad Genetics.29 In June 2010 it was reported that Myriad was halting its research programme into bevirimat in order to focus on oncology drugs.30 31

Phase III trials

Vivecon (MP-9055) is a maturation inhibitor which is Phase II trials. Previous trials have found that Vivecon may be effective for those resistant to NNRTIs and protease inhibitors.32

back to top NNRTIs

Recently approved

Etravirine – sold as Intelence – gained FDA approval in January 2008 and was approved in Europe the following August.33 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.34 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 III trials, 1.3% of participants developed severe rash, with 2% discontinuing Phase 3 trials due to rash.35

Rilpivirine gained FDA approval in May 2011.36 It is a once-daily pill to be taken in combination with other drugs, as part of first-line treatment for treatment-naive patients (those who have never taken antiretroviral therapy before). In the trials, rilpivirine (also known as Edurant) was proven to be as effective in lowering viral load as another NNRTI, efavirenz, but fewer patients stopped the treatment due to side effects. However, unlike with efavirenz, viral load at the beginning of treatment was found to impact the effectiveness of the drug. A lower viral load at the beginning of treatment with rilpivirine was associated with a greater likelihood of achieving an undetectable viral load. On the other hand, those with a higher viral load at the beginning of treatment did not respond to the treatment as well. Those who failed rilpvirine developed more drug resistance than those who failed efavirenz.37 38

Because rilpivirine is a low dose, once daily medication, it is easier to use it in the development of new fixed dose combinations (FDCs), which combine several different drugs into one pill. A new FDC comprising tenofovir, emtricitabine and rilpivirine (marketed as Complera) was approved by the FDA in 2011.39

Complera is the second once-daily fixed dose combination drug for treatment-naïve patients. The other is Atripla (which combines tenofovir, emtricitabine and efavirenz), approved in July 2006. A 2011 study found that individuals often switch from Atripla due to adverse side effects. It was reported that 1 in 5 patients discontinued Atripla within the first year, the most common reason cited was central nervous system toxicity.40 Trials for Complera aimed to establish whether or not rilpivirine would be as effective as efavirenz if taken in combination with emtricitabine and tenofovir by treatment naïve patients. In trials, viral load at start of treatment was linked to the likelihood of virological failure.41 Those who started Complera at high viral loads were more likely to experience virological failure and develop drug resistance than those taking the combination of efavirenz, emtricitabine and tenofovir at high viral loads. However, those taking Complera were reported to experience fewer side effects. Complera is not recommended for patients under 18 years old or with kidney problems.42

Phase II

Lersivirine is an NNRTI which has proven to have similar effectiveness at reducing viral load as efavirenz in a phase II trial among treatment naive patients.43 Nausea side effects were more reported with lersivirine but according to the phase IIb trials, less central nervous system side effects and rash were reported among those taking lersivirine. Another difference noted was that lersivirine was still effective against HIV with a certain mutation (position Y181), unlike efavirenz, etravirine and nevirapine.

back to top NRTIs

Phase II trials

KP-1461 is an NRTI that 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.44 However, in May 2009, the manufacturers announced optimistic findings from a subsequent study.45 In January 2011, a further phase II study showed that the mutation spectrum of HIV was altered in treatment-experienced patients, receiving KP1461 twice per day for 124 days.46 Further studies are expected to be released in the near future.

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 has stalled in development despite showing initially positive results. Avexa, the company developing the drug, announced in May 2010 that they would be ending development, explaining that they were unable to find an investment partner to back further development for this twice daily medication.47 However, this decision was reversed in July 2010 and Avexa is seeking to develop a new clinical trial to enable quick regulatory approval.48 49

Festinavir (previously OBP-601) is an NRTI related to stavudine but with less associated toxicity. Festinavir has been shown to be active against HIV resistant to NRTIs abacavir and tenofovir, and is therefore being investigated as a potential NRTI for those with multi-drug resistant strains of HIV.50

Nominet Winner 2012

References back to top

  1. FDA Consumer (January-February 2000) "Experimental Treatments? Unapproved but Not Always Unavailable"
  2. Aidsmap 'A to Z of investigational drugs'
  3. i-BASE/Treatment Action Group (2011, July) '2011 Pipeline Report' HIV, Hepatitis C Virus (HCV), and Tuberculosis Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development
  4. Pfizer (24 September 2007) "Pfizer's Celsentri Approved in the European Union, Providing a Novel Treatment Option for Treatment-Experienced HIV Patients"
  5. ViiV Healthcare (2009, 20th November, 'FDA Approves Expanded Use of Selzentry for Appropriate Patients Starting HIV Antiretroviral Therapy for the First Time'
  6. Bloomberg.com (26 October 2008) "Merck, Pfizer HIV Drugs Match Bristol's First-Use Treatment"
  7. Aidsmap (28 October 2008) "Vicriviroc: long-term safety concerns over cancers dispelled"
  8. [PDF] Merck (2010) 'January 20, 2010 - Frequently Asked Questions and Answers - (FAQs)'
  9. Aidsmap (2010, 15th July) 'Merck stops development of CCR5 inhibitor vicriviroc'
  10. ClinicalTrials.gov, accessed July 2009
  11. AIDSinfo (updated 16 October 2007) "PRO 140"
  12. AIDSmeds.com (2009, 15th September), 'ICAAC: Single-Dose PRO 140 Reduces HIV Levels for at least 10 Days'
  13. TheBody.com (2009, 22nd October), 'HIV Antiretrovirals in Development: An Update From ICAAC 2009'
  14. AIDSinfo (updated 8 August 2008) "TNX-355"
  15. TaiMed Biologics 'Ibalizumab (TMB-355)'
  16. Aidsmap (2011, March 1st) 'Attachment inhibitor BMS-663068 potent and well-tolerated in early study'
  17. Hosein SR 'I ANTI-HIV AGENTS: B. Cenicriviroc for inflammation and HIV' CATIE TreatmentUpdate 180 - 2010 Oct; 22(5): 2
  18. Hosein SR 'I ANTI-HIV AGENTS: B. Cenicriviroc for inflammation and HIV' CATIE TreatmentUpdate 180 - 2010 Oct; 22(5): 2
  19. Merck (21 December 2007) 'Isentress (raltegravir) from MSD, First Integrase Inhibitor, Approved by the European Union Commission'
  20. FDA, 'Isentress Label and Approval History
  21. AIDSinfo (updated 30 June 2008) "Raltegravir"
  22. FDA, 'Isentress Label and Approval History
  23. European Medicines Agency, 'Isentress European Public Assessment Report, product information'
  24. Joseph Eron et. al, (2011) CROI 2011 Paper no. 151LB 'DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II'
  25. nam / aidsmap 'Elvitegravir', accessed 2012
  26. ClinicalTrials.gov, accessed July 2009
  27. FDA (2012, August 27th), 'FDA approves new combination pill for HIV treatment for some patients'
  28. Panacos (26 October 2008) "Panacos Presents Phase 2b Bevirimat Data At The 48th Annual Interscience Conference On Antimicrobial Agents And Chemotherapy"
  29. Thepharmaletter (2009, 26th January) 'Myriad buys Panacos' bevirimat for $7m'
  30. Aidsmap (2010, 8th June) 'Myriad halts HIV maturation inhibitor drug programme'
  31. AIDSmeds (2010, 8th June) 'Myriad Genetics suspends its HIV maturation inhibitor program'
  32. Aidsmap 'Vivecon (MP-9055)'
  33. Tibotec (29 August 2008) "INTELENCE(TM) (Etravirine) Receives Marketing Authorisation in the European Union for HIV Combination Therapy"
  34. AIDSinfo (updated 25 January 2008) "Etravirine (TMC125)"
  35. Tibotec Therapeutics (2009, August), '"Dear Healthcare Professional" letter'
  36. FDA (2011, May) 'FDA approves new HIV treatment'
  37. Aidsmap (2011, May) 'Rilpivirine (Edurant) approved in United States'
  38. FDA (2011, May) 'FDA approves new HIV treatment'
  39. FDA (2011, August 10th) 'Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination'
  40. Zheng, J et. al (2011, September) 'Discontinuation of Tenofovir, Emtricitabine and Efavirenz as a Single Table Regime in HIV-1 Infected Individuals Naïve to Antiretroviral Therapy' Presentation H2-783 - 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago
  41. Gilead (2011, August 10th) 'U.S. Food and Drug Administration Approves Gilead Sciences' Complera(TM), a New Complete Once-Daily, Single-Tablet Regimen for HIV-1 Infection in Treatment-Naïve Adults'
  42. Gilead (2011, August 10th) 'U.S. Food and Drug Administration Approves Gilead Sciences' Complera(TM), a New Complete Once-Daily, Single-Tablet Regimen for HIV-1 Infection in Treatment-Naïve Adults'
  43. NATAP, 'Lersivirine, a New NNRTI, Versus Efavirenz as First-Line Therapy: 48 Weeks' 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
  44. AIDSmeds (17 June 2008) "Experimental HIV Drug Hits Snag"
  45. Koronis Pharmaceuticals (2009, 19th May) 'Koronis Pharmaceuticals' Scientific Advisory Board Confirms KP-1461 Clinical Drug Activity, HIV Ablation'
  46. Mullins J. et al, 2011, Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleside KP1461, PLoS One 6(1)
  47. Avexa (10 May 2010) "Avexa Closes Apricitabine Program"
  48. Avexa (23 July 2010) "Quarterly News Report for Shareholders for July 2010"
  49. EATG (2010, November 25th) 'Avexa secures meeting with US Food and Drug Administration on apricitabine'
  50. i-BASE/Treatment Action Group (2011, July) '2011 Pipeline Report' HIV, Hepatitis C Virus (HCV), and Tuberculosis Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development