Capravirine is an experimental anti-HIV drug which belongs to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of drugs. Other drugs in the NNRTI class are efavirenz (Sustiva) and nevirapine (Viramune).

Capravirine was developed by Shionogi & Co Ltd, a Japanese company, with Agouron-Pfizer, a United States pharmaceutical company. In 1998, Pfizer Inc. licensed the drug from Shionogi and began evaluating the drug's use in combination with other HIV drugs. Capravirine was formerly known as S-1153, and then as AG 1549.

In 2001, clinical trials of capravirine were suspended for over a year pending safety investigations by the United States Food and Drug Administration, following the discovery that the drug causes vasculitis (inflammation of the blood vessels) in dogs. Vasculitis may cause severe damage to the tissue supplied by inflamed blood vessels because blood cannot adequately reach the tissue.

Following a further period of development by Pfizer, capravirine's development was discontinued in July 2005. This decision was made after the drug performed poorly in clinical trials and studies showed that it had complex interactions with other HIV therapies.

Effectiveness of capravirine

Phase I trials suggested that capravirine is ten times more potent than currently available NNRTIs. A dosing study reported that monotherapy with 2100mg capravirine twice daily produced a 1.69 log₁₀ reduction in viral load after 10 days of treatment. This was equivalent to the viral load reduction in the triple therapy control arm (Hernandez 2000).

A phase II study in which NNRTI-experienced individuals with viral load rebound were randomised to receive one of two doses of capravirine or placebo plus nelfinavir (Viracept) and two new nucleoside reverse transcriptase inhibitors (NRTIs) found that 50% of the capravirine group had viral load below 400 copies/ml after 16 weeks. The median viral load reduction in the 2100mg group fell by 1.5 log₁₀, compared with 2 log₁₀ in the 1400mg group. However, there was no significant difference in the number of viral load rebounds between the placebo and capravirine groups in this study, and the 1400mg group generally perfumed better than the 2100mg group, driven by a higher rate of adverse events at the higher dose (Wolfe 2001).

Forty-eight week follow-up data from a similar study continued to show no difference between capravirine and placebo. Patients with NNRTI resistance were given 700 or 1400mg capravirine twice daily of placebo, alongside twice-daily nelfinavir and two NRTIs. All three arms had similar rates of virologic failure and viral load reductions, as well as similar side-effect profiles (Pesano 2005).

Sixteen of 36 patients in this study who chose to continue taking capravirine after the study was suspended still had undetectable viral load after 39 to 49 months of therapy (Hammond 2004). Among patients with detectable viraemia, 70% remained susceptible to capravirine despite high level resistance to efavirenz and nevirapine (Hammond 2003).

Capravirine was tested in studies where it was combined with drugs that are P450 CYP3A4 inhibitors, because these have been shown to boost plasma levels of the drug. Taking the drug with food also increases blood levels. A study in healthy volunteers showed that capravirine reduced lopinavir levels by 40%, but that lopinavir increased capravirine levels fivefold (Amantea 2003). This can affect the levels of other co-administered drugs, such as atorvastatin (Lipitor; Amantea 2004). However, adding saquinavir to a combination of capravirine and lopinavir / ritonavir (Kaletra) does not affect plasma concentrations of any of the drugs (Raber 2004).

Side-effects

Capravirine was well tolerated in the initial phase I study and there was no evidence of rash. Some clinicians feel that capravirine will need to be tested for longer to determine whether rash is a problem. Mild nausea, vomiting and headache were the most frequently reported side-effects.

In the phase II study a higher rate of nausea, vomiting and diarrhoea was seen in the 2100mg group. Consequently, the 1400mg dose has now been selected for further development.

Cross-resistance

Failure of one NNRTI tends to lead to cross-resistance to all currently available NNRTIs. However, capravirine may be active against viruses with resistance to efavirenz. Resistance to nevirapine (usually characterised by a mutation at codon Y181C) would render capravirine useless.

Capravirine is active against HIV variants with the single mutations K103N, V106A or L100I, which confer resistance to NNRTIs. However, a mutation at codon 181 or a dual mutation at codons 103 and 100 confer high level resistance to capravirine, calling into question its usefulness after NNRTI failure.

Test tube studies show that HIV with high level resistance to AZT (zidovudine, Retrovir) at codon 215 becomes re-sensitised to AZT if it develops capravirine resistance at codon L234I.

With long-term capravirine therapy as part of an antiretroviral drug combination, single mutations conferring high-level resistance do not develop rapidly, in contrast to the other NNRTIs (Hammond 2004).

Key research

Pesano (2005) randomised 179 patients with NNRTI resistance to receive 700 or 1400mg capravirine (CPV) or placebo twice daily, along with twice-daily nelfinavir (NFV) and 2 NRTIs. Baseline CD4 cell counts were 248, 249 and 206 cells/mm³ respectively, with a mean VL of 25,100 copies/ml. After 48 weeks, 15, 24 and 13% of the patients had failed to reduce VL by 0.5log₁₀ in 4 weeks or had rebounded after a 0.5log₁₀ fall in VL. The mean VL fall was 2.3, 2.4 and 2.1log₁₀. 43, 58 and 46% respectively had a VL under 400 copies/ml. However, of those with AZT and 3TC resistance at baseline, these values were 36, 54 and 31%, although these were not statistically significantly different. Diarrhoea was reported by 53, 65 and 49% of the patients respectively, and nausea by 27, 35 and 20%.

Raber (2004) assigned 28 healthy subjects to receive capravirine (CPV) 400mg plus lopinavir/ritonavir (LPV/r) 400/100mg twice daily or CPV 700mg plus LPV/r 533/133mg twice daily. Hard-gel saquinavir (SQV) 1000mg twice daily was added and blood samples were taken for pharmacokinetic analysis. Addition of SQV did not affect total exposure of CPV or LPV/r.

Jacobs conducted a drug interaction and dosing study to establish the interaction between this drug and the protease inhibitors. 29 people taking nelfinavir/3TC and AZT or d4T added capravirine for 28 days at doses from 175 to 1800mg twice daily. Nelfinavir increased capravirine levels by 2-fold. Most common new side-effects were nausea and diarrhoea.

Gewurz enrolled 36 antiretroviral-naive individuals into a dosing study of capravirine monotherapy (700mg, 1400mg, 2100mg twice daily or 700 mg or 1400mg thrice daily) compared with nelfinavir/AZT/3TC. Mean decreases in viral load ranged from -1.23 log (700mg twice daily) to -1.69 log for the 2100mg (twice daily) comparable to the triple therapy control arm.

Fujiwara reported that the effective concentration of capravirine is halved by single amino acid mutations associated with NNRTI resistance, including the Y181C mutation. Resistance to capravirine occurs after at least 2 substitutions, including F227L or L234I.

Potts (1999b) reported in vitro resistance research. Virus containing common NNRTI mutations K103N, V106A or L100I, or L100I/K103N or K103N/P225H was not significantly resistant to capravirine.

Dezube enrolled 54 patients in a Phase I dose-escalation and efficacy study. 25 received capravirine for 28 days with concomitant antiretroviral therapy. HIV RNA at baseline was below 200 copies in 1, whilst 11/25 had HIV RNA greater than 10,000 copies. Mean RNA decrease in those with detectable VL was -1.74 log (range 0.74-2.6 log). 12/25 had HIV RNA below 200 copies after 28 days. The mean CD4 cell increase was +122. No serious adverse events were reported; mild nausea and metallic taste were ameliorated by dosing with food.

Wolfe randomised 50 individuals failing an NNRTI containing regimen (HIV RNA > 2000) to capravirine 1400mg or 2100mg bid or placebo, plus nelfinavir 1250mg bid and two new NRTIs. After 16 weeks 75% of the 1400mg arm had HIV RNA less than 400 copies, compared to 50% of the 2100mg group. Four treatment failures were reported, 1 in the placebo arm and 2 in the 2100mg arm, and seven discontinuations occurred due to adverse events.

References

Amantea MA et al. Pharmacokinetic drug-drug interaction between capravirine, lopinavir/ritonavir and tenofovir in healthy volunteers. 42^nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract A-1609, 2003.

Amantea MA et al. Effect of capravirine (CPV) on the safety and pharmacokinetics (PK) of atorvastatin (ATV) with and without lopinavir/ritonavir (LPV/r) in healthy volunteers. Fifteenth International AIDS Conference, Bangkok, abstract TuPeB4630, 2004.

Dezube BJ et al. A second-generation non-nucleoside reverse transcriptase inhibitor (S-1153) for the treatment of HIV-1 infection. Twelfth World AIDS Conference, Geneva, abstract 12214, 1998.

Fujiwara T et al. S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1. Antimicrob Agents Chemother 42: 1340-1345, 1998.

Gewurz BE et al. Capravirine, a nonnucleoside reverse-transcriptase inhibitor in patients infected with HIV-1: a phase 1 study. J Infect Dis 190: 1957-1961, 2004.

Hammond JL et al. Long-term virological response to capravirine in HIV-infected NNRTI-experienced patients. 42^nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-871, 2003.

Hammond J et al. Analysis of time of failure genotype and phenotype from NNRTI-experienced patients treated with capravirine. Thirteenth International HIV Drug Resistance Workshop, Costa Adeje, abstract 15, 2004.

Hayashi S et al. Effects of fasting (F), high fat (H) and low fat (L) meals on the pharmacokinetics (PK) of a single oral dose of capravirine (CPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), in healthy volunteers. 40^th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 1667, 2000.

Jacobs M et al. Pharmacokinetic (PK) interaction of AG1549, a novel nonnucleoside reverse transcriptase inhibitor (NNRTI), with protease inhibitors (PI). Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 83, 2000.

Pesano R et al. 24-week safety, tolerability, and efficacy of capravirine as add-on therapy to nelfinavir and 2 nucleoside reverse transcriptase inhibitors in patients failing a nonnucleoside reverse transcriptase inhibitor-based regimen. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 555, 2005.

Potts KE et al. Antiviral activity and resistance profile of AG-1549, a novel HIV-1 non-nucleoside reverse transcriptase inhibitor. Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 12, 1999a.

Potts KE et al. Resistance profile of AG1549, a novel non-nucleoside reverse transcriptase inhibitor. Antivir Ther 4: S10, 1999b.

Raber SR et al. Addition of saquinavir (SQV) to a regimen of capravirine (CPV) plus lopinavir/ritonavir (LPV/r) does not alter systemic exposure of the antiretrovirals in healthy volunteers. Fifteenth International AIDS Conference, Bangkok, abstract TuPeB4631, 2004.

Wolfe P et al. Safety and efficacy of capravirine versus placebo in HIV-infected patients failing a non-nucleoside reverse transciptase inhibitor-containing regimen: results of a phase II, double blind, placebo controlled trial. Eighth Annual Conference on Retroviruses and Opportunistic Infections, abstract 323, 2001.