- Email: [email protected]
Targeting angiogenesis in pancreatic cancer
Comment
endpoint), although the placebo group showed a decline, the bosentan group did not show a statistically significant improvement and this is a limitation of the study. This result might simply indicate the improved exercise capacity at baseline in patients in WHO functional class II, which would make improvements difficult to show. WHO functional class and time to clinical worsening (both secondary endpoints) remained stable in the bosentan group, whereas they deteriorated in the placebo group. The investigators suggest, and we agree, that time to clinical worsening could be a useful primary endpoint in future trials, especially when studying patients with less severe disease. This study broadens the potential for bosentan as a treatment in pulmonary arterial hypertension, and the evidence presented by Galiè and colleagues should soon be translated into clinical practice. Despite theoretical benefits of an unblocked and stimulated endothelin B receptor—including natriuresis, diuresis, and endothelium-dependent vasodilation8—benefits for patients in WHO functional classes III and IV given bosentan are similar to those with more selective receptor antagonists of endothelin A, such as sitaxsentan7 and ambrisentan.9 Also of note, none of the clinical studies with endothelin-receptor antagonists in pulmonary arterial hypertension have yet shown a mortality benefit, except against historical controls. The scope of endothelin-receptor antagonism as a treatment option continues to extend beyond pul-
monary arterial hypertension (table) and includes chronic kidney disease,8 diastolic heart failure, resistant hypertension, and cancer. In some of these situations, an endothelin-receptor antagonist with endothelin A selectivity might theoretically offer additional benefits.8 We look forward to seeing progress in these and other areas in the near future. *Neeraj Dhaun, David J Webb Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK [email protected] DJW has acted as a consultant for Encysive, GlaxoSmithKline, Rosche, and Speedel Pharmaceuticals. ND has received research awards and is currently doing research with Encysive. 1 2 3
4
5
6 7
8
9
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–15. Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008; 31: 407–15. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled study (EARLY study). Lancet 2008; 371: 2093–100. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 1257–63. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119–23. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903. Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006; 47: 2049–56. Dhaun N, Pollock DM, Goddard J, Webb DJ. Selective and mixed endothelin receptor antagonism in cardiovascular disease. Trends Pharmacol Sci 2007; 28: 573–79. Galiè N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46: 529–35.
Targeting angiogenesis in pancreatic cancer Published Online May 30, 2008 DOI:10.1016/S01406736(08)60770-9 See Articles page 2101
2062
Prognosis for patients with advanced pancreatic cancer remains poor with a median survival of 6 months. The minimal effect of conventional cytotoxic therapy, including gemcitabine, on survival makes the development of new targeted therapies a priority. Tumour angiogenesis, in particular the well-studied signalling system mediated by vascular endothelial growth factor (VEGF), is a rational target in pancreatic cancer.1 The addition of bevacizumab, a monoclonal antibody against VEGFA, to conventional cytotoxic treatment is beneficial in several non-haematological cancers (eg, colorectal and lung cancers).2,3 However, a recent phase III trial (CALGB 80303) in patients with advanced pancreatic cancer found
no benefit for bevacizumab added to gemcitabine.4 The trial followed a single-arm phase II study of bevacizumab and gemcitabine that showed median survival of more than 8 months.5 The failure of CALGB 80303 to show a benefit for an anti-VEGF therapy cast doubt on the targeting of angiogenesis in advanced pancreatic cancer. Bevacizumab might have been likelier to succeed when combined with effective cytotoxic approaches on the basis of preclinical data6 and clinical experience in other cancers, such as colorectal.2 Another strategy in targeting tumour angiogenesis is to inhibit VEGF-receptormediated signalling with inhibitors of tyrosine kinase.7 www.thelancet.com Vol 371 June 21, 2008
Science Photo Library
Comment
Computer graphic of angiogenesis
Of the three receptors, VEGFR2 is the most biologically important because it is the primary receptor for VEGFA.8 Recent data support the use of tyrosine-kinase inhibitors in certain cancers that are resistant to conventional cytotoxic drugs (eg, sorafenib in kidney cancer).9 In today’s Lancet, Jean-Phillipe Spano and co-workers10 report a randomised phase II study in which they tested the addition of the tyrosine-kinase inhibitor axitinib to gemcitabine in patients with advanced pancreatic cancer. Axitinib is a small molecule that inhibits VEGF receptors 1–3 at picomolar concentrations.7 The drug also inhibits stromal and endothelial platelet-derived growthfactor receptor β at nanomolar concentrations, which might contribute to its antiangiogenic and antitumour effects.11 The study shows that progression-free, 1-year, and overall survival were longer in patients receiving axitinib than in those who received gemcitabine alone. The effect of axitinib was modest, but those patients with locally advanced disease or good performance status had a better improvement in survival. Results of this screening study are encouraging, but one has to consider the risk of false positivity inherent in such a study design. An ongoing phase III trial will more definitively determine whether axitinib improves survival.12 www.thelancet.com Vol 371 June 21, 2008
Is investment in clinical trials to test antiangiogenesis strategies in advanced pancreatic cancer worthwhile? The history of drug development in oncology provides examples of established therapies that were deemed ineffective at initial testing. There might be several reasons for the failure to show a benefit, including incomplete knowledge of biology or inappropriate experimental design. The complexity and cross-talk of signalling networks controlling angiogenesis13 can hinder approaches that target a single molecule or one pathway.4,14 Furthermore, cancers undergoing angiogenesis express proangiogenic growth factors and receptors other than VEGF and VEGFR.15 However, small-molecule tyrosine-kinase inhibitors inhibit multiple molecules7 with better access than large monoclonal antibodies to pancreatic tumours, which are characterised by fibrosis and hypovascularisation. The targeting of multiple nodes within angiogenic pathways could offer another strategy that has not been fully studied. Angiogenesis remains a valid target to be systematically studied in pancreatic cancer. In addition to the phase III trial of axitinib, another phase III study is testing the combination of the VEGFA-binding protein aflibercept in combination with gemcitabine.16 Within the next 3–5 years these studies will improve knowledge of targeting angiogenesis in pancreatic cancer but are unlikely to produce major breakthroughs in therapy for reasons discussed above. In view of the biological effect of angiogenesis on tumour progression and invasion, one could hypothesise that therapies will be more beneficial in earlier stages of disease, including after tumour resection. We need an improved understanding of the complex interactions between pancreatic cancer cells and their specific microenvironment to better plan the next generation of clinical trials that encompass the cancer process rather than a single target. Preclinical and clinical pilot studies must also validate profiling to select patients on the basis of biomarkers that predict response (or resistance) to targeted agents. Close collaboration between clinical and basic scientists in partnership with the drug industry is key for future success. Philip A Philip Karmanos Cancer Center, Detroit, MI 48201, USA [email protected] I declare that I have no conflict of interest.
2063
Comment
1 2
3
4
5
6
7 8 9
Kleeff J, Beckhove P, Esposito I, et al. Pancreatic cancer microenvironment. Int J Cancer 2007; 121: 699–705. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–42. Sandler A, Gray R, Perry PC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 2006; 355: 2542–50. Kindler HL, Niedzwiecki D, Hollis D, et al. A double-blind, placebocontrolled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB). J Clin Oncol 2007; 25 (suppl): 4508 (abstr). Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005; 23: 8033–40. Duffy JP, Eibl G, Reber HA, Hines OJ. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer 2003; 2: 12. Cabebe E, Fisher GA. Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer. Expert Opin Investig Drugs 2007; 16: 467–76. Buchler P, Reber HA, Buchler MW, Friess H, Hines OJ. VEGF-RII influences the prognosis of pancreatic cancer. Ann Surg 2002; 236: 738–49. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–34.
10
11
12
13
14
15 16
Spano J-P, Chodkiewicz C, Maurel J, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008; published online May 30. DOI:10.1016/S0140-6736(08)60661-3. Song S, Ewald JE, Stallcup W, Werb Z, Bergers G. PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 2005; 7: 870–79. Pfizer. Randomized study of gemcitabine plus AG-013736 versus gemcitabine for advanced pancreatic cancer. April, 2008. http:// clinicaltrials.gov/ct2/show/NCT00471146?term=axitinib&rank=7 (accessed May 23, 2008). Abdollahi A, Schwager C, Kleeff J, et al. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci USA 2007; 104: 12 890–95. Friess H, Langrehr JM, Oettle H, et al. A randomized multi-center phase II trial of the angiogenesis inhibitor cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer 2006; 6: 285. Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2003; 2: 8. Sanofi-Aventis. Aflibercept compared to placebo in terms of efficacy in patients treated with gemcitabine for metastatic pancreatic cancer. April, 2008. http://clinicaltrials.gov/ct2/show/NCT00574275?term=aflibercept& rank=3 (accessed May 23, 2008).
Reassessing the hypothesis on STI control for HIV prevention Two randomised trials of HIV prevention, one in Tanzania1 and the other multicentre (HPTN 039) trial reported in today’s Lancet,2 assessed the effects of suppressing herpes simplex virus type 2 (HSV-2) with aciclovir 400 mg twice daily in initially HIV-uninfected HSV-2-seropositive participants. Both trials found no effect of HSV-2 suppression on HIV acquisition. This finding is unexpected, since many observational studies suggest that HSV-2 and genital ulcer disease are risk factors for HIV infection; so it
Science Photo Library
See Articles page 2109
Herpes simplex virus particle
2064
was plausible that herpes suppression might reduce HIV acquisition.3 Surprisingly, the Tanzanian trial only reported nine clinically observed genital ulcers or vesicular lesions in the intervention group (2·3%) and six in the control group (1·4%).1 In the HPTN 039 multicentre trial, clinically observed genital ulcer disease was reduced by 47% and HSV-2-positive ulcers by 63% in the aciclovir group,2 but the investigators comment that this efficacy was less than expected. African studies into causes of genital ulcer disease have failed to identify known sexually transmitted pathogens in a high proportion of clinical ulcers,4,5 so ulceration unrelated to HSV-2 could have diluted the expected effect of aciclovir. Also, the aciclovir regimen might be inadequate to completely suppress herpetic ulceration or subclinical HSV-2 reactivation.1,2 Compliance with aciclovir was high in the multicentre trial,2 but moderate in the Tanzanian study in which only a third of a subset of 144 participants had detectable aciclovir in their urine at 12 and 24 months.1 The apparent discrepancy between the observational studies compared with the negative results of randomised trials for HSV-2 suppression is similar to the discrepancy between observational and trial evidence about bacterial sexually transmitted infections and HIV. Observational data suggested that bacterial sexually transmitted infections increase HIV acquisition and genital HIV shedding,6 leading to the hypothesis that control of such www.thelancet.com Vol 371 June 21, 2008
endpoint), although the placebo group showed a decline, the bosentan group did not show a statistically significant improvement and this is a limitation of the study. This result might simply indicate the improved exercise capacity at baseline in patients in WHO functional class II, which would make improvements difficult to show. WHO functional class and time to clinical worsening (both secondary endpoints) remained stable in the bosentan group, whereas they deteriorated in the placebo group. The investigators suggest, and we agree, that time to clinical worsening could be a useful primary endpoint in future trials, especially when studying patients with less severe disease. This study broadens the potential for bosentan as a treatment in pulmonary arterial hypertension, and the evidence presented by Galiè and colleagues should soon be translated into clinical practice. Despite theoretical benefits of an unblocked and stimulated endothelin B receptor—including natriuresis, diuresis, and endothelium-dependent vasodilation8—benefits for patients in WHO functional classes III and IV given bosentan are similar to those with more selective receptor antagonists of endothelin A, such as sitaxsentan7 and ambrisentan.9 Also of note, none of the clinical studies with endothelin-receptor antagonists in pulmonary arterial hypertension have yet shown a mortality benefit, except against historical controls. The scope of endothelin-receptor antagonism as a treatment option continues to extend beyond pul-
monary arterial hypertension (table) and includes chronic kidney disease,8 diastolic heart failure, resistant hypertension, and cancer. In some of these situations, an endothelin-receptor antagonist with endothelin A selectivity might theoretically offer additional benefits.8 We look forward to seeing progress in these and other areas in the near future. *Neeraj Dhaun, David J Webb Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK [email protected] DJW has acted as a consultant for Encysive, GlaxoSmithKline, Rosche, and Speedel Pharmaceuticals. ND has received research awards and is currently doing research with Encysive. 1 2 3
4
5
6 7
8
9
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–15. Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008; 31: 407–15. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled study (EARLY study). Lancet 2008; 371: 2093–100. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 1257–63. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119–23. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903. Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006; 47: 2049–56. Dhaun N, Pollock DM, Goddard J, Webb DJ. Selective and mixed endothelin receptor antagonism in cardiovascular disease. Trends Pharmacol Sci 2007; 28: 573–79. Galiè N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46: 529–35.
Targeting angiogenesis in pancreatic cancer Published Online May 30, 2008 DOI:10.1016/S01406736(08)60770-9 See Articles page 2101
2062
Prognosis for patients with advanced pancreatic cancer remains poor with a median survival of 6 months. The minimal effect of conventional cytotoxic therapy, including gemcitabine, on survival makes the development of new targeted therapies a priority. Tumour angiogenesis, in particular the well-studied signalling system mediated by vascular endothelial growth factor (VEGF), is a rational target in pancreatic cancer.1 The addition of bevacizumab, a monoclonal antibody against VEGFA, to conventional cytotoxic treatment is beneficial in several non-haematological cancers (eg, colorectal and lung cancers).2,3 However, a recent phase III trial (CALGB 80303) in patients with advanced pancreatic cancer found
no benefit for bevacizumab added to gemcitabine.4 The trial followed a single-arm phase II study of bevacizumab and gemcitabine that showed median survival of more than 8 months.5 The failure of CALGB 80303 to show a benefit for an anti-VEGF therapy cast doubt on the targeting of angiogenesis in advanced pancreatic cancer. Bevacizumab might have been likelier to succeed when combined with effective cytotoxic approaches on the basis of preclinical data6 and clinical experience in other cancers, such as colorectal.2 Another strategy in targeting tumour angiogenesis is to inhibit VEGF-receptormediated signalling with inhibitors of tyrosine kinase.7 www.thelancet.com Vol 371 June 21, 2008
Science Photo Library
Comment
Computer graphic of angiogenesis
Of the three receptors, VEGFR2 is the most biologically important because it is the primary receptor for VEGFA.8 Recent data support the use of tyrosine-kinase inhibitors in certain cancers that are resistant to conventional cytotoxic drugs (eg, sorafenib in kidney cancer).9 In today’s Lancet, Jean-Phillipe Spano and co-workers10 report a randomised phase II study in which they tested the addition of the tyrosine-kinase inhibitor axitinib to gemcitabine in patients with advanced pancreatic cancer. Axitinib is a small molecule that inhibits VEGF receptors 1–3 at picomolar concentrations.7 The drug also inhibits stromal and endothelial platelet-derived growthfactor receptor β at nanomolar concentrations, which might contribute to its antiangiogenic and antitumour effects.11 The study shows that progression-free, 1-year, and overall survival were longer in patients receiving axitinib than in those who received gemcitabine alone. The effect of axitinib was modest, but those patients with locally advanced disease or good performance status had a better improvement in survival. Results of this screening study are encouraging, but one has to consider the risk of false positivity inherent in such a study design. An ongoing phase III trial will more definitively determine whether axitinib improves survival.12 www.thelancet.com Vol 371 June 21, 2008
Is investment in clinical trials to test antiangiogenesis strategies in advanced pancreatic cancer worthwhile? The history of drug development in oncology provides examples of established therapies that were deemed ineffective at initial testing. There might be several reasons for the failure to show a benefit, including incomplete knowledge of biology or inappropriate experimental design. The complexity and cross-talk of signalling networks controlling angiogenesis13 can hinder approaches that target a single molecule or one pathway.4,14 Furthermore, cancers undergoing angiogenesis express proangiogenic growth factors and receptors other than VEGF and VEGFR.15 However, small-molecule tyrosine-kinase inhibitors inhibit multiple molecules7 with better access than large monoclonal antibodies to pancreatic tumours, which are characterised by fibrosis and hypovascularisation. The targeting of multiple nodes within angiogenic pathways could offer another strategy that has not been fully studied. Angiogenesis remains a valid target to be systematically studied in pancreatic cancer. In addition to the phase III trial of axitinib, another phase III study is testing the combination of the VEGFA-binding protein aflibercept in combination with gemcitabine.16 Within the next 3–5 years these studies will improve knowledge of targeting angiogenesis in pancreatic cancer but are unlikely to produce major breakthroughs in therapy for reasons discussed above. In view of the biological effect of angiogenesis on tumour progression and invasion, one could hypothesise that therapies will be more beneficial in earlier stages of disease, including after tumour resection. We need an improved understanding of the complex interactions between pancreatic cancer cells and their specific microenvironment to better plan the next generation of clinical trials that encompass the cancer process rather than a single target. Preclinical and clinical pilot studies must also validate profiling to select patients on the basis of biomarkers that predict response (or resistance) to targeted agents. Close collaboration between clinical and basic scientists in partnership with the drug industry is key for future success. Philip A Philip Karmanos Cancer Center, Detroit, MI 48201, USA [email protected] I declare that I have no conflict of interest.
2063
Comment
1 2
3
4
5
6
7 8 9
Kleeff J, Beckhove P, Esposito I, et al. Pancreatic cancer microenvironment. Int J Cancer 2007; 121: 699–705. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–42. Sandler A, Gray R, Perry PC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 2006; 355: 2542–50. Kindler HL, Niedzwiecki D, Hollis D, et al. A double-blind, placebocontrolled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB). J Clin Oncol 2007; 25 (suppl): 4508 (abstr). Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005; 23: 8033–40. Duffy JP, Eibl G, Reber HA, Hines OJ. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer 2003; 2: 12. Cabebe E, Fisher GA. Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer. Expert Opin Investig Drugs 2007; 16: 467–76. Buchler P, Reber HA, Buchler MW, Friess H, Hines OJ. VEGF-RII influences the prognosis of pancreatic cancer. Ann Surg 2002; 236: 738–49. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–34.
10
11
12
13
14
15 16
Spano J-P, Chodkiewicz C, Maurel J, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008; published online May 30. DOI:10.1016/S0140-6736(08)60661-3. Song S, Ewald JE, Stallcup W, Werb Z, Bergers G. PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 2005; 7: 870–79. Pfizer. Randomized study of gemcitabine plus AG-013736 versus gemcitabine for advanced pancreatic cancer. April, 2008. http:// clinicaltrials.gov/ct2/show/NCT00471146?term=axitinib&rank=7 (accessed May 23, 2008). Abdollahi A, Schwager C, Kleeff J, et al. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci USA 2007; 104: 12 890–95. Friess H, Langrehr JM, Oettle H, et al. A randomized multi-center phase II trial of the angiogenesis inhibitor cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer 2006; 6: 285. Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2003; 2: 8. Sanofi-Aventis. Aflibercept compared to placebo in terms of efficacy in patients treated with gemcitabine for metastatic pancreatic cancer. April, 2008. http://clinicaltrials.gov/ct2/show/NCT00574275?term=aflibercept& rank=3 (accessed May 23, 2008).
Reassessing the hypothesis on STI control for HIV prevention Two randomised trials of HIV prevention, one in Tanzania1 and the other multicentre (HPTN 039) trial reported in today’s Lancet,2 assessed the effects of suppressing herpes simplex virus type 2 (HSV-2) with aciclovir 400 mg twice daily in initially HIV-uninfected HSV-2-seropositive participants. Both trials found no effect of HSV-2 suppression on HIV acquisition. This finding is unexpected, since many observational studies suggest that HSV-2 and genital ulcer disease are risk factors for HIV infection; so it
Science Photo Library
See Articles page 2109
Herpes simplex virus particle
2064
was plausible that herpes suppression might reduce HIV acquisition.3 Surprisingly, the Tanzanian trial only reported nine clinically observed genital ulcers or vesicular lesions in the intervention group (2·3%) and six in the control group (1·4%).1 In the HPTN 039 multicentre trial, clinically observed genital ulcer disease was reduced by 47% and HSV-2-positive ulcers by 63% in the aciclovir group,2 but the investigators comment that this efficacy was less than expected. African studies into causes of genital ulcer disease have failed to identify known sexually transmitted pathogens in a high proportion of clinical ulcers,4,5 so ulceration unrelated to HSV-2 could have diluted the expected effect of aciclovir. Also, the aciclovir regimen might be inadequate to completely suppress herpetic ulceration or subclinical HSV-2 reactivation.1,2 Compliance with aciclovir was high in the multicentre trial,2 but moderate in the Tanzanian study in which only a third of a subset of 144 participants had detectable aciclovir in their urine at 12 and 24 months.1 The apparent discrepancy between the observational studies compared with the negative results of randomised trials for HSV-2 suppression is similar to the discrepancy between observational and trial evidence about bacterial sexually transmitted infections and HIV. Observational data suggested that bacterial sexually transmitted infections increase HIV acquisition and genital HIV shedding,6 leading to the hypothesis that control of such www.thelancet.com Vol 371 June 21, 2008