MIV-310 reduces HIV viral load in patients failing multiple antiretroviral therapy: results from a 4-week phase II study
AIDS: Volume 18(9) 18 June 2004 pp 1299-1304
Katlama, Christinea; Ghosn, Jadea; Tubiana, Rolanda; Wirden, Marcb; Valantin, Marc-Antoinea; Harmenberg, Johanc; Mårdh, Göranc; Öberg, Boc; Calvez, Vincentb
From the aDépartement des Maladies Infectieuses et Tropicales/INSERM E0214, and bLaboratoire de Virologie, Hôpital Pitié-Salpêtrière, Paris, France; and c Medivir AB, Huddinge, Sweden.
"...MIV-310 (alovudine, Medivir AB, Sweden), at a once-daily oral dose of 7.5 mg, was added to the ongoing antiretroviral regimen, which was not changed during the study period...The addition of MIV-310 resulted in a rapid decrease in the plasma HIV-1-RNA load, by a median of -1.13 log10 (range -0.31 to -2.66) from baseline to week 4 in the 15 patients... Longer-term MIV-310 administration has previously been linked to reversible, apparently dose-dependent haematological adverse effects, especially at doses above 10 mg a day. However, these evaluations were conducted in patients with advanced disease in the pre-HAART era. Given the urgent need for new drugs active on multiresistant HIV strains, specifically those harbouring TAM, the present results support the re-evaluation of MIV-310 as a potent HIV medication... The magnitude of the observed effect suggests that lower doses might also be effective while at the same time offering adequate safety during long-term use."
Drug resistance is a major and increasing issue in the treatment of HIV infection. Combination therapies with the available nucleoside analogue reverse transcriptase (NRTI), non-nucleoside reverse transcriptase inhibitors and protease inhibitors fail in many patients. The main factor involved in the onset of resistance is persistent viral replication during therapy. Even low-level viraemia can be associated with the selection of strains with several mutations conferring drug resistance. Furthermore, the proportion of new cases of HIV infection that involve drug-resistant viruses is increasing, from 3.4% in 1995-1998 to 12.4% in 1999-2000. Although resistance testing is useful when selecting drugs to overcome virological failure, some patients with multiple drug resistance have no effective therapeutic alternative.
MIV-310 (3¢-deoxy-3¢fluorothymidine) is an NRTI initially tested in the early 1990s. Development was halted because of safety concerns (mainly haematological events at a dosage above 10 mg/day) and because MIV-310 had no obvious advantage over zidovudine.
MIV-310 was recently tested against a large panel of multiresistant HIV strains in four independent laboratories, and was found to have a potent and unique profile of efficacy in vitro. Given the urgent need for new drugs active on resistant HIV strains, we conducted an open pilot trial of MIV-310 in patients in whom multidrug antiretroviral therapy was failing and who had documented genotypic resistance.
Background: Drug resistance is an increasing problem in the treatment of HIV infection. MIV-310 (alovudine), a nucleoside reverse transcriptase inhibitor, potently inhibits the replication of highly mutated strains of HIV in vitro. We examined the efficacy of MIV-310 in highly pretreated patients.
Methods: In a phase II pilot study, 15 patients failing a current antiretroviral therapy with at least two thymidine-associated mutations (TAM) were given MIV-310 7.5 mg once daily for 4 weeks, in addition to their ongoing treatment. The primary endpoint was the plasma viral load reduction at week 4.
MIV-310 (alovudine, 3¢-deoxy-3¢-fluorothymidine; Medivir AB, Sweden), at a once-daily oral dose of 7.5 mg, was added to the ongoing antiretroviral regimen, which was not changed during the study period. The 7.5 mg dose was selected to avoid haematological toxicity, as judged from the previous study , and to be inhibitory even to the most resistant HIV variants. The patients were seen weekly during the 4-week treatment period and one month after treatment for physical examination, plasma HIV-1-RNA load assay, CD4 cell count, haematology, liver, kidney and pancreatic function tests and assessment of adverse events.
---(4. Flexner C, van der Horst C, Jacobson MA, Powderly W, Duncanson F, Ganes D, et al. Relationship between plasma concen trations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials. J Infect Dis 1994, 170:1394-1403.)
Results: At baseline, the median viral load was 3.93 log10 copies/ml and the median CD4 cell count was 360 cells/mm3. After 4 weeks of MIV-310 administration, the median decrease in viral load was -1.13 log10.
Interestingly, the median reduction was only -0.57 log10 in the four patients on stavudine, contrasting with a median reduction of -1.88 log10 in the 11 patients not receiving concomitant stavudine. The viral load fell by a median of -1.60 log10 in patients with two to three TAM (n = 7), and by -1.88 log10 in patients with four or five TAM (n = 8). The viral load rebounded in all patients after MIV-310 cessation. No mutations were found in the reverse transcriptase coding region during MIV-310 treatment. MIV-310 was well tolerated, with no serious adverse events and no treatment withdrawals.
Conclusion: MIV-310 7.5 mg/day efficiently reduced the HIV viral load in patients failing a multiple-drug regimen. Further studies with different dosages and longer administration times are urgently needed.
This was an open-label, single-arm pilot study designed to evaluate the virological benefit of adding MIV-310 to a failing highly active antiretroviral therapy regimen in patients harbouring HIV strains resistant to NRTI.
HIV-infected patients older than 18 years were eligible for inclusion if they met the following criteria: plasma HIV-1-RNA load between 1000 and 50 000 copies/ml; a stable antiretroviral regimen consisting of three to five drugs (excluding zidovudine for potential additional haematological toxicity) for at least 12 weeks before inclusion; and at least two thymidine-associated mutations (TAM) at positions 41, 67, 70, 210 or 215 of the reverse transcriptase (RT) gene, as shown by genotypic testing. Other inclusion criteria were a CD4 cell count greater than 100 cells/mm3, neutrophils greater than 1500/mm3, leukocytes greater than 3000/mm3, platelets 100 000/mm3 or greater, haemoglobin greater than 10 g/l, serum creatinine of 1.0 or less than the upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase 2.5 or less than ULN and serum bilirubin 1.25 or less than ULN. Patients with pancreatitis or evidence of chronic viral hepatitis were excluded, as were patients with acute opportunistic infections and patients receiving chemotherapy for malignancies. Patients treated with hydroxyurea, zidovudine, ganciclovir, recombinant erythropoietin, probenecid or dipyridamidole were also excluded.
Criteria for evaluation and sample size
The primary endpoint was the change in plasma HIV-RNA load from baseline to week 4. Secondary endpoints included clinical and biological tolerability and CD4 cell count changes from baseline to week 4. The required sample size of 12 patients was calculated to detect a minimum decrease of 0.5 log10 with a power of 80% and a type I error of 0.05 in a two-tailed test. Therefore, 15 patients were enrolled in order to avoid a dilution effect if certain patients were unassessable.
Fourteen men and one woman were enrolled from October 2001 to March 2002, all were included in the analysis. The median age was 41 years (31-51), and the median time on an NRTI-containing antiretroviral regimen was 9 years (5-12). The median CD4 cell count at baseline was 360 cells/mm3 (123-603) and the median HIV-RNA load was 3.93 log10 (2.9-4.7). The median number of NRTI resistance-associated mutations at baseline was seven (range three to 10) and the median number of TAM was four (range two to five).
Changes in plasma HIV-1-RNA load and CD4 cell counts
The addition of MIV-310 resulted in a rapid decrease in the plasma HIV-1-RNA load, by a median of -1.13 log10 (range -0.31 to -2.66) from baseline to week 4 in the 15 patients (P < 0.001, analysis of variance and Friedman's test). Interestingly, the median decrease in the four patients receiving stavudine was -0.57 log10 (P = 0.1250), contrasting with the -1.88 log10 reduction in the 11 patients who were not receiving concomitant stavudine (P = 0.001). At week 4, the plasma viral load was below 400 copies/ml in nine of the 15 patients overall (60%), and in eight of the 11 who were not taking stavudine (73%).
The viral load fell by -1.60 log10 in the seven patients with two or three TAM, and by -1.88 log10 in the eight patients with four or five TAM. The viral load always rebounded to baseline values in all patients after the cessation of MIV-310. No new mutations in the RT gene were detected and no significant change in MIV-310 50% inhibitory concentration values was observed between baseline and week 4. The CD4 cell count rose by a median of 9 cells/mm3 between baseline and week 4.
Safety and tolerability
Treatment with MIV-310 7.5 mg a day, in combination with other antiretroviral agents, was generally well tolerated. No serious adverse events occurred during the study period. The most noteworthy adverse events were fatigue (n = 4), loss of appetite (n = 3), transaminase elevation (n = 2, one grade 1 and one grade 2), and a fall in the haemoglobin level (one patient). MIV-310 was never prematurely withdrawn.
Discussion by authors
This pilot study demonstrates that the addition of MIV-310 to a failing antiretroviral regimen is able to reduce the plasma HIV-1-RNA load by -1.88 log10 after 4 weeks in patients who did not receive stavudine. All the patients treated with MIV-310 had previously been exposed to all classes of antiretroviral drugs for lengthy periods. At baseline, viral genotyping showed a median of four TAM and seven NRTI mutations per patient, reflecting multiple drug resistance. This in-vivo efficacy of MIV-310 against certain strains with representative TAM of HIV-1 is consistent with data previously obtained in vitro at four independent laboratories. Importantly, we found that MIV-310 50% inhibitory concentration values were unchanged between baseline and week 4 of treatment and that no new mutations that could be attributed to selection by MIV-310 were found in this short-term study. As mutations were analysed by whole-sample population sequencing, the possibility that low frequency variants with new mutations have escaped detection cannot be excluded. The lesser efficacy of MIV-310 in patients also receiving stavudine points to an interaction between the two drugs. Such an interaction has previously been described between stavudine and zidovudine (which is structurally related to MIV-310). As patients on zidovudine were excluded in view of the potential for haematological toxicity of both zidovudine and MIV-310, a potential interaction between zidovudine and MIV-310 can not be excluded at present.MIV-310 appears to be more effective than abacavir and tenofovir, on the basis of similar studies in which these drugs were added to failing multidrug regimens. Abacavir and tenofovir reduced the HIV-1-RNA load by approximately 0.5-0.6 log10, when used in separate studies of similar design in comparison with baseline or with control patients. Furthermore, the antiviral activity of these latter agents is dependent on the number of resistance mutations. In contrast, MIV-310 reduced viral load by more than 1.5 log10 in patients with up to five TAM. The speed at which the initial reduction in viral load occurs has been shown to correlate with the subsequent efficacy and durability of the virological response. Therefore, the reduction in plasma HIV-RNA levels obtained after one week of MIV-310 therapy (approximately 1 log10 in non-stavudine patients) is very encouraging. A previous study of MIV-310 monotherapy showed marked antiviral efficacy at all dose levels, including the lowest dose of approximately 2 mg a day. As all patients except one harboured HIV strains containing the M184V mutation, the possibility that this mutation may increase sensitivity towards MIV-310 in parallel to similar findings for zidovudine cannot be excluded.
MIV-310 was well tolerated in this one-month study, and no unexpected adverse effects occurred. However, no conclusions can be drawn on safety or tolerability given the short treatment period, the small number of patients, and the absence of a placebo group in the study. Longer-term MIV-310 administration has previously been linked to reversible, apparently dose-dependent haematological adverse effects, especially at doses above 10 mg a day. However, these evaluations were conducted in patients with advanced disease in the pre-HAART era. Given the urgent need for new drugs active on multiresistant HIV strains, specifically those harbouring TAM, the present results support the re-evaluation of MIV-310 as a potent HIV medication.
In conclusion, MIV-310 7.5 mg a day markedly reduced HIV-1 viral load in 15 patients harbouring multiple mutations conferring resistance to NRTI. The magnitude of the observed effect suggests that lower doses might also be effective while at the same time offering adequate safety during long-term use.
Sponsorship: This study was sponsored by Medivir AB.
The study was presented in part at the XIVth International AIDS Conference, Barcelona, July 2002, and the XIth International HIV Drug Resistance Workshop, Seville, July 2002.
July 2003 Press Release from BI
Boehringer Ingelheim and Medivir sign agreement for novel HIV/AIDS Antiviral -MIV-310, as a possible treatment for multi-drug resistant patients-
Ingelheim, Germany/Huddinge, Sweden, 15 July 2003 - Boehringer Ingelheim and Medivir today announced that Medivir has out-licensed its innovative HIV antiviral MIV-310 to Boehringer Ingelheim.
MIV-310 is an extremely potent inhibitor of reverse transcriptase and belongs to the nucleoside analogue class (NRTI). Currently, it is in phase II clinical development. In contrast to conventional nucleoside analogues on the market, preclinical and clinical results show that MIV-310 has a unique activity against multi-drug resistant HIV-1.
Under the terms of the agreement, Boehringer Ingelheim will make upfront and milestone payments to Medivir totaling up to 122 million euro in the event that all development and performance milestones are met. Medivir will also receive a double-digit royalty on product sales. Boehringer Ingelheim receives exclusive global marketing rights, except for the Nordic countries (Sweden, Denmark, Finland, Norway, and Iceland), which are retained by Medivir. Responsibility for pharmaceutical and clinical development rests with Boehringer Ingelheim.
There are currently over 40 million HIV/AIDS positive people, of which 1.4 million are in the industrialized world. A significant proportion of these have drug-resistant virus. In a newly published study, it was revealed that 70 percent of patients in the industrialized world are virus-resistant to current NRTI antivirals.
"For Medivir, it is an important milestone, and a clear sign of our excellence within polymerase research, again to be able to out-licence an HIV project", commented Lars Adlersson, CEO of Medivir. "It is rewarding to be able to contribute new hope to people living with resistant HIV".
"We are pleased to have concluded this agreement and look forward to collaborating with Medivir on MIV-310", said Dr Andreas Barner, Member of the Board of Managing Directors at Boehringer Ingelheim, responsible for Research & Development and Medicine. "Together with the marketed non-nucleoside reverse transcriptase inhibitor Viramune, and the protease inhibitor tipranavir, currently in phase III of clinical development, MIV-310 will complement Boehringer Ingelheim's HIV drug development portfolio."
About Boehringer Ingelheim
The Boehringer Ingelheim Corporation is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany it operates globally with 156 affiliates in 44 countries and a total of about 32,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
In 2002, Boehringer Ingelheim posted net sales of 7.6 billion euro while spending about one fifth of net sales in its largest business segment Prescription Medicines on research and development.
For more information on Boehringer Ingelheim, please see the international Internet website www.boehringer-ingelheim.com.
The Medivir Group
Medivir is an innovative, specialist research corporation that produces and develops pharmaceuticals. The company is located in Huddinge, Sweden and Cambridge, UK. Medivir's research is focused on developing new drug compounds based on proteases and polymerases as target enzymes.
The group comprises Medivir AB, the subsidiaries Medivir UK Ltd. and the CCS group. The CCS group will change ownership from 1 July 2003. Medivir has been quoted on the Stockholm Stock Exchange since 1996 and will be included on the Attract40 list from the 1 July 2003.
Medivir's research portfolio includes projects against hepatitis, HIV, jaundice, shingles, cold sores, osteoporosis, RA (rheumatoid arthritis), asthma and MS (multiple sclerosis). Medivir has four projects in clinical development phases, two of which are entering phase III after completing phase II. One project is in phase I and one is in phase II. In the first stage of preclinical pharmaceutical discovery, Medivir has some ten activities in explorative activities; the second, lead identification, encompasses three projects. The third stage, optimization, has one project, and two projects entering this phase. One project-MV026048-is in preclinical development, the stage closest to clinical development.
For additional information, please see Medivir's website www.medivir.com