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New Antiretrovirals New Antiretrovirals: What Is on the Way? pg255-259 5/16/05 10:15 AM Page 255 NEW ANTIRETROVIRALS NEW ANTIRETROVIRALS: WHAT IS ON THE WAY? Despite the present number of available antiretrovirals, there continues to be a need for new medications with improved tolerability and activity against resistant HIV strains. This article reviews antiretrovirals available in North America and Europe, not yet registered in South Africa, as well as promising new compounds in clinical development. NEW NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) Tenofovir Once daily with unique NRTI-resistance profile FTC Once daily cytidine analogue SPD 754 Cytidine analogue with activity against M184V mutation D-D4FC Cytidine analogue with activity against NRTI-resistance strains ROBIN WOOD Amdoxovir Guanidine analogue with activity against NRTI-resistance BSc, BM , DTM&H, MMed, FCP(SA) strains Professor of Medicine Groote Schuur Hospital Tenofovir disoproxil fumarate is a nucleotide analogue of adenosine 5’- Director monophosphate. It was registered in the USA in 2001, initially for patients Desmond Tutu HIV Centre failing previous therapies and more recently extended to first-line therapy. The Institute of Infectious Disease and Molecular Medicine major route of elimination is renal and it is dosed once daily. When co- University of Cape Town administered with didanosine it is recommended that the dose of didanosine be reduced from 400 mg to 250 mg per day. When combined with lamivudine Robin Wood completed his undergraduate training at Oxford and London University, (3TC) or FTC, tenofovir has shown ARV efficacy in both ARV-experienced and and carried out postgraduate training in -naïve patients. Resistance is associated with a K65R mutation, which occurs internal medicine at the University of infrequently in patients receiving tenofovir. Tenofovir has the least mitochondrial Cape Town, and infectious diseases toxicity of the presently registered NRTIs. training at Stanford Medical School, California. Since 1993 he has supervised FTC is a cytidine analogue closely related to 3TC but is administered once daily. the first dedicated HIV clinic in the Western Cape at Somerset Hospital. His The potency and resistance profiles of FTC and 3TC are similar. major research interests are in the fields of infectious diseases and HIV. SPD 754 is a de-oxycytidine analogue that has in vitro activity against HIV strains with the 3TC resistance-associated M184V mutation. In treatment-naïve patients, a dose-dependent antiviral activity was shown, with no development of new RT mutations. SPD 754 has the least mitochondrial toxicity when compared with 9 other NRTIs. D-D4FC is another de-oxycytidine analogue with in vitro activity against NRTI- resistant HIV strains. In vivo activity was demonstrated in both treatment-naïve and treatment-experienced patients with virus highly resistant to other NRTIs. Amdoxovir (DAPD) is a guanine analogue with a potentially attractive resistance profile. The addition of DAPD to optimised therapy in heavily pre- treated patients achieved a 0.5 log decline in 58% of subjects. May 2005 Vol.23 No.5 CME 255 pg255-259 5/16/05 10:15 AM Page 258 NEW ANTIRETROVIRALS When combined with shown in both treatment-naïve and study of 3 doses of tipranavir/ritonavir lamivudine (3TC) or FTC, NNRTI-experienced patients. (500/100 mg, 500/200 mg and 750/200 mg) in heavily pre-treated tenofovir has shown ARV NEW PROTEASE INHIBITORS (PIs) patients achieved a 1.0 log reduction efficacy in both ARV- in viral load in those receiving the 2 experienced and higher dosages; however, the 500/100 mg dose was safer and -naïve patients. Atazanavir Once daily PI with better tolerated. ‘lipid-friendly’ profile A-681799 Extended PI- There is considerable TMC-114 has potent in vitro and in resistance profile vivo activity against PI-resistant strains. interest in second- Fosamprenavir Pro-drug of A study of 3 regimens of TMC-114, generation NNRTIs with amprenavir with with ritonavir substituted in heavily activity against nevirapine- lower pill burden pre-treated patients for a currently and efavirenz-resistant HIV Tipranavir Extended PI- failing PI, showed a 1.2 - 1.5 log resistance profile strains. decrease in viral load at 14 days. TMC-114 Extended PI- resistance profile PIs are associated with NEW CLASSES OF ARVs deranged lipid and glucose There is a need for new PIs with metabolism, which has distinct resistance profiles and activity against highly PI-resistant HIV strains. motivated development of Fusion inhibitors PIs are associated with deranged lipid T-20 Peptide binding to ‘metabolic friendly’ PIs. and glucose metabolism, which has viral gp41-blocking motivated development of ‘metabolic membrane fusion friendly’ PIs. T-1249 Activity against NEW NON-NUCLEOSIDE T-20-resistant virus REVERSE TRANSCRIPTASE Atazanavir is an azopeptide PI free INHIBITORS (NNRTIs) of cholesterol and triglyceride CCR5 Inhibitors abnormalities. The main side-effect is GW87314 Blocker of a human an increase in unconjugated bilirubin, co-receptor for HIV which is related to serum drug level binding Capravirine 2nd generation and glucoronidation enzyme genotype SCH-C/SCH-D Blocker of a human NNRTI with (Gilbert’s trait). Once-daily dosing and co-receptor for HIV extended a benign metabolic profile make this binding resistance profile an attractive first-line PI, particularly in UK-427857 Blocker of a human TMC-125 Active against patients with increased cardiovascular co-receptor for HIV highly NNRTI- risk factors. binding resistant virus A-681799 is structurally related to Integrase inhibitor S-1360 First-generation There is considerable interest in atazanavir, with in vitro activity against lopinavir-resistant virus. blocker of third second-generation NNRTIs with HIV-encoded activity against nevirapine- and Fosamprenavir is a pro-drug of enzyme efavirenz-resistant HIV strains. amprenavir and is formulated into 476 mg tablets. Its side-effect profile is New classes of ARVs include fusion Capravirine is a second-generation similar to that of the parent drug. inhibitors, chemokine co-receptor NNRTI that requires multiple mutations There is a considerably decreased pill blockers and integrase inhibitors. to develop in vitro high-level burden (6 - 8 tablets) compared with While there is considerable clinical resistance. In patients failing NNRTI amprenavir (16 tablets). Once-daily experience with the fusion inhibitor therapy, capravirine in combination dosing is possible when fosamprenavir T-20, which was registered for use in with nelfinavir and 2 NRTIs was is combined with ritonavir. the USA and Europe in 2003, co- superior to placebo, nelfinavir and 2 receptor blockers and integrase NRTIs. Tipranavir is a non-peptidic HIV inhibitors are entering phase III trials protease inhibitor, with interest driven and phase I/II clinical studies, TMC-125 is a di-aminopyrimidine by in vitro data indicating activity respectively. NNRTI with potent in vitro activity against highly PI-resistant strains of against HIV, including clinical isolates HIV. The dosing and formulation have Fusion inhibitors with high-level resistance to current been problematical and therapeutic T-20 or enfuvirtide is a large NNRTIs. In vivo activity has been boosting with ritonavir is necessary. A polypeptide molecule that inhibits HIV 258 CME May 2005 Vol.23 No.5 pg255-259 5/16/05 10:15 AM Page 259 NEW ANTIRETROVIRALS fusion with T-cells. Membrane fusion SCH-C is a small-molecule CCR5 inhibitors. The use of combinations of requires conformational changes in inhibitor with in vitro activity against integrase inhibitors offers the prospect viral gp41, which T-20 blocks by CCR5 and CCX4/R5 duotropic of robust inhibition of the third HIV binding to this ‘spring-like’ molecule. strains. A dose-dependent response enzyme target. The usual dosage of T-20 is 90 mg has been shown in HIV-infected (1 ml) administered by subcutaneous patients. CONCLUSION injection twice daily; it should be augmented with other potent drugs. UK427857 has also shown dose- Manufacture of T-20 is complex, related antiviral activity in ART continues to evolve rapidly, with requiring multiple steps, and it is likely antiretroviral therapy (ART)-naïve increasing survival of patients. to remain a costly drug. individuals, with predominately CCR5- Chronic management not only requires tropic HIV. Receptor-binding modelling potent antiviral effect but also user- T-1249 is a second-generation fusion studies indicate a dose of 100 mg bd friendly and less toxic regimens. The inhibitor with greater in vitro potency or equivalent daily dose for long-term number of new compounds being than T-20 and activity against viral treatment. developed and particularly the strains that are resistant to T-20. increase in drug targets increases Monotherapy studies in heavily pre- Integrase inhibitors options to fight this highly mutable treated patients demonstrated a 1.3 Integrase, the third enzyme encoded virus. log decline in viral load after 14 days in the HIV genome, has remained an with a 25 mg twice-daily dose. Further reading elusive target of drug development. A Guidelines for use of antiretroviral agents in HIV- Unfortunately T-1249 development has number of compounds have been 1 infected adults and adolescents. Department of been discontinued. shown to inhibit this enzyme in vitro Health and Human Services. http://aidsinfo.nih.gov/guidelines/adult/aa but many of them have shown high Chemokine receptor inhibitors 102904.pdf toxicity. S-1360, a diketo-acid New therapies. British HIV Association guide- lines for the treatment of HIV-infected adults with GSK-873140 is a spirodiketo- derivative, is a DNA strand transfer antiretroviral therapy. piperizine CCR5 antagonist with integrase inhibitor and was generally http://www.bhiva.org/guidelines/2003/hiv/ potent in vitro activity. In HIV-infected well tolerated in healthy volunteers. new-therapies.html individuals with a CD4 > 200 and Dipyrimidine derivatives have also predominantly CCR5-tropic virus at been shown to inhibit the binding of baseline, a dose-related antiviral effect integrase with viral DNA and was shown. constitute a second class of integrase IN A NUTSHELL There is a need for new ARTs.
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