Comment
8
9
10
11
12
Zajicek J, Ball S, Wright D, et al, for the CUPID Investigator Group. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol 2013; 12: 857–65. Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5: 256–66. Popescu V, Agosta F, Hulst HE, et al, for the MAHNIMS Study Group. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013; 84: 1082–91. Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 2013; 75: 43–49. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; published online March 19. http://dx.doi.org/10.1016/S01406736(13)62242-4.
13
14 15
Sormani MP, Cutter G, Comi G, et al. Evaluating the relationship between laquinimod’s effects on relapses and disability progression. 29th European Committee for Treatment and Research in Multiple Sclerosis; Cophenhagen, Denmark; Oct 2–5, 2013; p1080. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001; 57: 1239–47. Pickin M, Cooper CL, Chater T, et al. The multiple sclerosis risk sharing scheme monitoring study—early results and lessons for the future. BMC Neurol 2009; 9: 1.
FLAMINGO: how much rosier can antiretroviral therapy get? In the SPRING-21 trial, dolutegravir showed noninferiority to raltegravir, another integrase inhibitor, in antiretroviral-naive adults with HIV-1 infection. In the SINGLE trial,2 dolutegravir showed superiority over a non-nucleoside reverse transcriptase inhibitor, efavirenz. The next obvious step of the dolutegravir targeted strategy was to compare dolutegravir with a boosted protease inhibitor such as darunavir plus ritonavir. The comparison between dolutegravir and a boosted protease inhibitor is particularly interesting because boosted protease inhibitors are very potent and, by contrast with raltegravir and efavirenz,3 extremely resilient to HIV resistance development even when used as monotherapy.4 In The Lancet, Bonaventura Clotet and colleagues present the FLAMINGO study,5 in which 484 antiretroviralnaive HIV-infected patients were randomly assigned to receive two nucleos(t)ide reverse transcriptase inhibitors (tenofovir–emtricitabine or abacavir–lamivudine) plus either dolutegravir (50 mg) or the boosted protease inhibitor darunavir (800 mg) plus ritonavir (100 mg). After 48 weeks of follow-up, more than 80% of patients in each group achieved virological suppression (217 [90%] patients receiving dolutegravir and 200 [83%] patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL, adjusted difference 7·1% [95% CI 0·9–13·2]), and no patient developed drug resistance. It is difficult to imagine a better outcome for a clinical trial in a disease that just two decades ago did not have an effective treatment. In a prespecified secondary analysis, dolutegravir also showed superiority to darunavir plus ritonavir. The www.thelancet.com Vol 383 June 28, 2014
data suggest that superiority was driven both by better tolerability (nine [3%] patients in the dolutegravir group and 20 [9%] patients in the darunavir plus ritonavir group discontinued for non-virological reasons) and better efficacy (virological success in 217 [90%] patients in the dolutegravir group vs 200 [83%] patients in the darunavir plus ritonavir group), especially in the 25% of patients who started with viral loads greater than 100 000 copies per mL. But is dolutegravir really superior to darunavir plus ritonavir? This is a difficult question to answer for various reasons. First, FLAMINGO5 is an open-label clinical trial with two pills a day taken by patients in the dolutegravir group versus four pills a day taken by those in the comparator group (darunavir plus ritonavir). The openlabel design might have led to patients, disappointed with their treatment assignment, choosing not to continue. In fact, six patients withdrew in the darunavir plus ritonavir group very early on compared with the one patient who withdrew in the dolutegravir group.
Published Online April 1, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60447-5 See Articles page 2222
N
Treatment emergent resistance NRTI
Integrase
NNRTI
Protease
ABC/3TC-dolutegravir2
414
0
0
··
··
TDF/FTC (or ABC/3TC)-dolutegravir1
411
0
0
··
··
TDF/FTC (or ABC/3TC)-dolutegravir5
242
0
0
··
··
TDF/FTC/efavirenz2
419
1
··
4
··
TDF/FTC (or ABC/3TC)-raltegravir1
411
4
1
··
··
TDF/FTC (or ABC/3TC)-darunavir/r5
242
0
··
··
0
Data are number of patients. TDF=tenofovir. FTC=emtricitabine. ABC=abacavir. 3TC=lamivudine. NRTI=nucleotide reverse transcriptase inhibitors. NNRTI=non-nucleotide reverse transcriptase inhibitors.
Table 1: Treatment emergent resistance in phase 3 clinical trials of dolutegravir
2191
Comment
Second, results cannot be automatically extrapolated to all antiretroviral-naive patients because most patients recruited were young white men whose median CD4 cell count was almost 400 cells per μL. This cell count was within the threshold for starting therapy for most guidelines6 but above the mean CD4 cell count at HIV diagnosis in patients in high-income countries (336 cells per μL).7 Third, integrase inhibitors tend to reduce viral load very rapidly, often reaching undetectability in less than 8 weeks, whereas protease inhibitors tend to cause a more gradual decrease.8 This effect could lead to patients starting with a very high viral load in the darunavir plus ritonavir group still having a detectable but falling viral load, even after 48 weeks. They might have reached a very low viraemia of 50–200 copies per mL but not virological suppression at that time, even though viral load might have subsequently become undetectable. The detailed viral load results of 48-week outcomes in patients with very high viral loads at initiation (>100 000 copies per mL and >500 000 copies per mL), and the 96-week study data are analyses important in understanding the outcomes. Fourth, since no patient developed resistance after virological failure in either group, the superiority of dolutegravir does not translate into an advantage with respect to preserving future treatment options. Finally, a third of the patients in the control group received abacavir plus lamivudine and darunavir plus ritonavir. This combination has not been widely studied before, and data about its efficacy are scarce, especially in patients with high viral loads. To patients and clinicians these criticisms might seem rhetorical since dolutegravir has been shown to be as effective, if not more, than a comparator regimen that requires a higher pill burden, longer time to achieve viral suppression, more drug–drug interactions, and less favourable lipid changes. The only apparent management issue with dolutegravir is its effect on lowering the estimated, but not true, glomerular filtration rate due to its action on inhibiting organic cation transporter-1 in the tubule and decreasing creatine secretion.9 Although this issue is not a true renal toxic effect, and in FLAMINGO5 no participant developed grade 3–4 increase in creatinine, physicians have to be aware of this phenomenon, especially in patients with underlying renal disease, so that any changes in creatinine can be interpreted correctly. Another note of caution is 2192
that long-term follow-up is needed to continue to look out for adverse events. In FLAMINGO,5 the development of resistance was zero in both treatment groups. Dolutegravir is the first drug outside the boosted protease inhibitor family not to be associated with development of resistance in clinical trials of antiretroviral-naive patients (table). However, whether this similarity with boosted protease inhibitors means that dolutegravir can be used as monotherapy or dual therapy along with a single nucleos(t)ide reverse transcriptase inhibitor or nonnucleoside reverse transcriptase inhibitor is unknown. The results of FLAMINGO5 also support the idea that we are entering the integrase inhibitor era in HIV therapeutics. Integrase inhibitors are on the recommended list of drugs for initiation of antiretroviral therapy in most major guidelines,6,10 and the US Department of Health and Human Services has now included dolutegravir.11 It might not be too long before some of the well established nonnucleosides and protease inhibitors are relegated to the alternative list by guideline panels. The dominance of the non-nucleoside efavirenz as a drug of choice in HIV is being questioned because of its common shortterm and potentially long-term neuropsychiatric sideeffects, including the increase risk of suicidality12 and the increasing availability of other better-tolerated drugs, which also come coformulated as a regimen in a single pill. However, the rosy future of integrase inhibitors could be threatened by generic drugs. Guidelines do not usually take into account cost-effectiveness, and as more drugs come off patent and budgets become restrained, will new drugs be affordable? One strategy might be to start patients on a generic regimen and switch them to an integrase inhibitor if they develop side-effects or intolerance. This might be an economic solution, but a robust discussion is needed regarding the acceptability of such approaches when drugs such as dolutegravir have shown superior trial outcomes over current standards of care. *Anton L Pozniak, Jose R Arribas HIV Directorate, Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK (ALP); Imperial College London, London, UK (ALP); and HIV Unit, Hospital La Paz, IdiPAZ, Madrid, Spain (JRA) [email protected] ALP receives advisory fees, speaker’s fees, or grant support from Viiv, Tibotec, Janssen, Bristol-Myers Squibb, Gilead Sciences, Merck inc, and Tobira. JRA receives advisory fees, speaker’s fees, or grant support from Viiv, Tibotec, Janssen, Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Inc, and Tobira.
www.thelancet.com Vol 383 June 28, 2014
Comment
1
2 3
4
5
6
Raffi F, Rachlis A, Stellbrink HJ, et al; SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381: 735–43. Walmsley S, Antela A, Clumeck N, et al. Dolutegravir plus abacavir/lamivudine for the initial treatment of HIV-1 infection. N Engl J Med 2013; 369: 1807–18. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374: 796–806. Mathis S, Khanlari B, Pulido F, et al. Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. PLoS One 2011; 6: e22003. Clotet B, Feinberg J, van Lunzen J, et al, on behalf of the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; published online April 1. http://dx.doi.org/10.1016/S0140-6736(14)60084-2. US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adult and adolescents. Washington, DC: US Department of Health and Human Services, 2012. http://aidsinfo.nih.gov/ contentfiles/lvguidelines/adultandadolescentgl.pdf (accessed Feb 14, 2014).
7
8 9
10
11
12
Lesko CR, Cole SR, Zinski A, Poole C, Mugavero MJ. A systematic review and meta-regression of temporal trends in adult CD4+ cell count at presentation to HIV care, 1992–2011. Clin Infect Dis 2013; 57: 1027–37. Arribas JR, Eron J. Advances in antiretroviral therapy. Curr Opin HIV AIDS 2013; 8: 341–49. Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and paraaminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2013; 75: 990–96. European AIDS Clinical Society. EACS treatment guidelines version 7.0 October, 2013. Brussels: European AIDS Clinical Society, 2013. http://www.eacsociety. org/Portals/0/Guidelines_Online_131014.pdf (accessed Feb 14, 2014). AIDS info. Recommendation on integrase inhibitor use in antiretroviral treatment-naive HIV-infected individuals from the HHS panel on antiretroviral guidelines for adults and adolescents. Oct 30, 2013. http:// aidsinfo.nih.gov/news/1392/hhs-panel-on-antiretroviral-guidelines-foradults-and-adolescents-updates-recommendations-on-insti-basedregimens-for-art-naive-individuals (accessed Feb 17, 2014). Mollan K, Smurzynski M, Na L, et al. Hazard of suicidality in patients randomly assigned to efavirenz for initial treatment of HIV-1: a cross-study analysis conducted by the AIDS Clinical Trials Group (ACTG). IDWeek 2013. Oct 2–6, 2013. San Francisco. Abstr 670.
Acute pericarditis is a common and usually benign disease and is assessed by auscultation, electrocardiograph, echocardiography, blood markers (C-reactive protein, troponin), and chest radiography. In high-income countries, idiopathic or so-called viral pericarditis is the commonest final diagnosis (>80% of cases). The major specific causes are tuberculosis, neoplasms, cardiac surgery, and systemic autoimmune diseases. Some features are independent predictors of a specific cause—eg, fever more than 38°C, subacute course, large pericardial effusion or cardiac tamponade, and failure of non-steroidal anti-inflammatory drugs (NSAIDs). These two latter features are associated with increased risk of complications during follow-up.1 After the first episode of acute pericarditis, recurrences are frequent (20–50%). Although the pathogenesis of pericarditis is poorly understood, it might be related to spontaneous or viral-induced autoimmune or autoinflammatory disorders.2 Idiopathic recurrent pericarditis shares features with autoinflammatory diseases such as familial Mediterranean fever, with liver or pleuropulmonary involvement in 8–30% of patients.3,4 However, the overall long-term prognosis for patients with idiopathic recurrent pericarditis is very good, with an estimated risk of constriction of less than 1%.5 Aspirin and NSAIDs are the cornerstone of treatment and should be used until symptoms disappear and C-reactive protein www.thelancet.com Vol 383 June 28, 2014
concentration normalises. Corticosteroid treatment is a risk factor for recurrences and should be restricted to patients with intolerance, contraindication, or failure of NSAIDs, using low doses with slow tapering. Alternative drugs have been proposed, including azathioprine, highdose intravenous human immunoglobulins, interleukin-1 receptor antagonist, and other immunosuppressive treatments. Pericardiectomy has been proposed for patients refractory to drug treatment. Clinicians have long been sceptical about the use of colchicine for treatment of acute pericarditis. The first support for colchicine came from open-label trials.6,7 The COlchicine for PEricarditis (COPE) trial6 showed that, for patients with a first episode of acute pericarditis, 3 months of colchicine treatment as an adjunct to conventional treatment decreased recurrences and symptom persistence at 72 h. The efficacy of colchicine in addition to NSAIDs for acute pericarditis was shown by the ICAP trial.8 In this multicentre, double-blind study, adults with acute pericarditis were randomly assigned to receive either colchicine for 3 months or placebo, in addition to NSAIDs. The primary study outcome—incessant or recurrent pericarditis— occurred in 20 (16·7%) patients in the colchicine group versus 45 (37·5%) in the placebo group.8 Colchicine also significantly improved symptom persistence at 72 h, remissions at 1 week, the number of recurrences per patient, and number of admissions to hospital.8
ZEPHYR/Science Photo Library
Colchicine for treatment of acute or recurrent pericarditis
Published Online March 30, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60113-6 See Articles page 2232
2193
8
9
10
11
12
Zajicek J, Ball S, Wright D, et al, for the CUPID Investigator Group. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol 2013; 12: 857–65. Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5: 256–66. Popescu V, Agosta F, Hulst HE, et al, for the MAHNIMS Study Group. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013; 84: 1082–91. Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 2013; 75: 43–49. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; published online March 19. http://dx.doi.org/10.1016/S01406736(13)62242-4.
13
14 15
Sormani MP, Cutter G, Comi G, et al. Evaluating the relationship between laquinimod’s effects on relapses and disability progression. 29th European Committee for Treatment and Research in Multiple Sclerosis; Cophenhagen, Denmark; Oct 2–5, 2013; p1080. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001; 57: 1239–47. Pickin M, Cooper CL, Chater T, et al. The multiple sclerosis risk sharing scheme monitoring study—early results and lessons for the future. BMC Neurol 2009; 9: 1.
FLAMINGO: how much rosier can antiretroviral therapy get? In the SPRING-21 trial, dolutegravir showed noninferiority to raltegravir, another integrase inhibitor, in antiretroviral-naive adults with HIV-1 infection. In the SINGLE trial,2 dolutegravir showed superiority over a non-nucleoside reverse transcriptase inhibitor, efavirenz. The next obvious step of the dolutegravir targeted strategy was to compare dolutegravir with a boosted protease inhibitor such as darunavir plus ritonavir. The comparison between dolutegravir and a boosted protease inhibitor is particularly interesting because boosted protease inhibitors are very potent and, by contrast with raltegravir and efavirenz,3 extremely resilient to HIV resistance development even when used as monotherapy.4 In The Lancet, Bonaventura Clotet and colleagues present the FLAMINGO study,5 in which 484 antiretroviralnaive HIV-infected patients were randomly assigned to receive two nucleos(t)ide reverse transcriptase inhibitors (tenofovir–emtricitabine or abacavir–lamivudine) plus either dolutegravir (50 mg) or the boosted protease inhibitor darunavir (800 mg) plus ritonavir (100 mg). After 48 weeks of follow-up, more than 80% of patients in each group achieved virological suppression (217 [90%] patients receiving dolutegravir and 200 [83%] patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL, adjusted difference 7·1% [95% CI 0·9–13·2]), and no patient developed drug resistance. It is difficult to imagine a better outcome for a clinical trial in a disease that just two decades ago did not have an effective treatment. In a prespecified secondary analysis, dolutegravir also showed superiority to darunavir plus ritonavir. The www.thelancet.com Vol 383 June 28, 2014
data suggest that superiority was driven both by better tolerability (nine [3%] patients in the dolutegravir group and 20 [9%] patients in the darunavir plus ritonavir group discontinued for non-virological reasons) and better efficacy (virological success in 217 [90%] patients in the dolutegravir group vs 200 [83%] patients in the darunavir plus ritonavir group), especially in the 25% of patients who started with viral loads greater than 100 000 copies per mL. But is dolutegravir really superior to darunavir plus ritonavir? This is a difficult question to answer for various reasons. First, FLAMINGO5 is an open-label clinical trial with two pills a day taken by patients in the dolutegravir group versus four pills a day taken by those in the comparator group (darunavir plus ritonavir). The openlabel design might have led to patients, disappointed with their treatment assignment, choosing not to continue. In fact, six patients withdrew in the darunavir plus ritonavir group very early on compared with the one patient who withdrew in the dolutegravir group.
Published Online April 1, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60447-5 See Articles page 2222
N
Treatment emergent resistance NRTI
Integrase
NNRTI
Protease
ABC/3TC-dolutegravir2
414
0
0
··
··
TDF/FTC (or ABC/3TC)-dolutegravir1
411
0
0
··
··
TDF/FTC (or ABC/3TC)-dolutegravir5
242
0
0
··
··
TDF/FTC/efavirenz2
419
1
··
4
··
TDF/FTC (or ABC/3TC)-raltegravir1
411
4
1
··
··
TDF/FTC (or ABC/3TC)-darunavir/r5
242
0
··
··
0
Data are number of patients. TDF=tenofovir. FTC=emtricitabine. ABC=abacavir. 3TC=lamivudine. NRTI=nucleotide reverse transcriptase inhibitors. NNRTI=non-nucleotide reverse transcriptase inhibitors.
Table 1: Treatment emergent resistance in phase 3 clinical trials of dolutegravir
2191
Comment
Second, results cannot be automatically extrapolated to all antiretroviral-naive patients because most patients recruited were young white men whose median CD4 cell count was almost 400 cells per μL. This cell count was within the threshold for starting therapy for most guidelines6 but above the mean CD4 cell count at HIV diagnosis in patients in high-income countries (336 cells per μL).7 Third, integrase inhibitors tend to reduce viral load very rapidly, often reaching undetectability in less than 8 weeks, whereas protease inhibitors tend to cause a more gradual decrease.8 This effect could lead to patients starting with a very high viral load in the darunavir plus ritonavir group still having a detectable but falling viral load, even after 48 weeks. They might have reached a very low viraemia of 50–200 copies per mL but not virological suppression at that time, even though viral load might have subsequently become undetectable. The detailed viral load results of 48-week outcomes in patients with very high viral loads at initiation (>100 000 copies per mL and >500 000 copies per mL), and the 96-week study data are analyses important in understanding the outcomes. Fourth, since no patient developed resistance after virological failure in either group, the superiority of dolutegravir does not translate into an advantage with respect to preserving future treatment options. Finally, a third of the patients in the control group received abacavir plus lamivudine and darunavir plus ritonavir. This combination has not been widely studied before, and data about its efficacy are scarce, especially in patients with high viral loads. To patients and clinicians these criticisms might seem rhetorical since dolutegravir has been shown to be as effective, if not more, than a comparator regimen that requires a higher pill burden, longer time to achieve viral suppression, more drug–drug interactions, and less favourable lipid changes. The only apparent management issue with dolutegravir is its effect on lowering the estimated, but not true, glomerular filtration rate due to its action on inhibiting organic cation transporter-1 in the tubule and decreasing creatine secretion.9 Although this issue is not a true renal toxic effect, and in FLAMINGO5 no participant developed grade 3–4 increase in creatinine, physicians have to be aware of this phenomenon, especially in patients with underlying renal disease, so that any changes in creatinine can be interpreted correctly. Another note of caution is 2192
that long-term follow-up is needed to continue to look out for adverse events. In FLAMINGO,5 the development of resistance was zero in both treatment groups. Dolutegravir is the first drug outside the boosted protease inhibitor family not to be associated with development of resistance in clinical trials of antiretroviral-naive patients (table). However, whether this similarity with boosted protease inhibitors means that dolutegravir can be used as monotherapy or dual therapy along with a single nucleos(t)ide reverse transcriptase inhibitor or nonnucleoside reverse transcriptase inhibitor is unknown. The results of FLAMINGO5 also support the idea that we are entering the integrase inhibitor era in HIV therapeutics. Integrase inhibitors are on the recommended list of drugs for initiation of antiretroviral therapy in most major guidelines,6,10 and the US Department of Health and Human Services has now included dolutegravir.11 It might not be too long before some of the well established nonnucleosides and protease inhibitors are relegated to the alternative list by guideline panels. The dominance of the non-nucleoside efavirenz as a drug of choice in HIV is being questioned because of its common shortterm and potentially long-term neuropsychiatric sideeffects, including the increase risk of suicidality12 and the increasing availability of other better-tolerated drugs, which also come coformulated as a regimen in a single pill. However, the rosy future of integrase inhibitors could be threatened by generic drugs. Guidelines do not usually take into account cost-effectiveness, and as more drugs come off patent and budgets become restrained, will new drugs be affordable? One strategy might be to start patients on a generic regimen and switch them to an integrase inhibitor if they develop side-effects or intolerance. This might be an economic solution, but a robust discussion is needed regarding the acceptability of such approaches when drugs such as dolutegravir have shown superior trial outcomes over current standards of care. *Anton L Pozniak, Jose R Arribas HIV Directorate, Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK (ALP); Imperial College London, London, UK (ALP); and HIV Unit, Hospital La Paz, IdiPAZ, Madrid, Spain (JRA) [email protected] ALP receives advisory fees, speaker’s fees, or grant support from Viiv, Tibotec, Janssen, Bristol-Myers Squibb, Gilead Sciences, Merck inc, and Tobira. JRA receives advisory fees, speaker’s fees, or grant support from Viiv, Tibotec, Janssen, Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Inc, and Tobira.
www.thelancet.com Vol 383 June 28, 2014
Comment
1
2 3
4
5
6
Raffi F, Rachlis A, Stellbrink HJ, et al; SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381: 735–43. Walmsley S, Antela A, Clumeck N, et al. Dolutegravir plus abacavir/lamivudine for the initial treatment of HIV-1 infection. N Engl J Med 2013; 369: 1807–18. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374: 796–806. Mathis S, Khanlari B, Pulido F, et al. Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. PLoS One 2011; 6: e22003. Clotet B, Feinberg J, van Lunzen J, et al, on behalf of the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; published online April 1. http://dx.doi.org/10.1016/S0140-6736(14)60084-2. US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adult and adolescents. Washington, DC: US Department of Health and Human Services, 2012. http://aidsinfo.nih.gov/ contentfiles/lvguidelines/adultandadolescentgl.pdf (accessed Feb 14, 2014).
7
8 9
10
11
12
Lesko CR, Cole SR, Zinski A, Poole C, Mugavero MJ. A systematic review and meta-regression of temporal trends in adult CD4+ cell count at presentation to HIV care, 1992–2011. Clin Infect Dis 2013; 57: 1027–37. Arribas JR, Eron J. Advances in antiretroviral therapy. Curr Opin HIV AIDS 2013; 8: 341–49. Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and paraaminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2013; 75: 990–96. European AIDS Clinical Society. EACS treatment guidelines version 7.0 October, 2013. Brussels: European AIDS Clinical Society, 2013. http://www.eacsociety. org/Portals/0/Guidelines_Online_131014.pdf (accessed Feb 14, 2014). AIDS info. Recommendation on integrase inhibitor use in antiretroviral treatment-naive HIV-infected individuals from the HHS panel on antiretroviral guidelines for adults and adolescents. Oct 30, 2013. http:// aidsinfo.nih.gov/news/1392/hhs-panel-on-antiretroviral-guidelines-foradults-and-adolescents-updates-recommendations-on-insti-basedregimens-for-art-naive-individuals (accessed Feb 17, 2014). Mollan K, Smurzynski M, Na L, et al. Hazard of suicidality in patients randomly assigned to efavirenz for initial treatment of HIV-1: a cross-study analysis conducted by the AIDS Clinical Trials Group (ACTG). IDWeek 2013. Oct 2–6, 2013. San Francisco. Abstr 670.
Acute pericarditis is a common and usually benign disease and is assessed by auscultation, electrocardiograph, echocardiography, blood markers (C-reactive protein, troponin), and chest radiography. In high-income countries, idiopathic or so-called viral pericarditis is the commonest final diagnosis (>80% of cases). The major specific causes are tuberculosis, neoplasms, cardiac surgery, and systemic autoimmune diseases. Some features are independent predictors of a specific cause—eg, fever more than 38°C, subacute course, large pericardial effusion or cardiac tamponade, and failure of non-steroidal anti-inflammatory drugs (NSAIDs). These two latter features are associated with increased risk of complications during follow-up.1 After the first episode of acute pericarditis, recurrences are frequent (20–50%). Although the pathogenesis of pericarditis is poorly understood, it might be related to spontaneous or viral-induced autoimmune or autoinflammatory disorders.2 Idiopathic recurrent pericarditis shares features with autoinflammatory diseases such as familial Mediterranean fever, with liver or pleuropulmonary involvement in 8–30% of patients.3,4 However, the overall long-term prognosis for patients with idiopathic recurrent pericarditis is very good, with an estimated risk of constriction of less than 1%.5 Aspirin and NSAIDs are the cornerstone of treatment and should be used until symptoms disappear and C-reactive protein www.thelancet.com Vol 383 June 28, 2014
concentration normalises. Corticosteroid treatment is a risk factor for recurrences and should be restricted to patients with intolerance, contraindication, or failure of NSAIDs, using low doses with slow tapering. Alternative drugs have been proposed, including azathioprine, highdose intravenous human immunoglobulins, interleukin-1 receptor antagonist, and other immunosuppressive treatments. Pericardiectomy has been proposed for patients refractory to drug treatment. Clinicians have long been sceptical about the use of colchicine for treatment of acute pericarditis. The first support for colchicine came from open-label trials.6,7 The COlchicine for PEricarditis (COPE) trial6 showed that, for patients with a first episode of acute pericarditis, 3 months of colchicine treatment as an adjunct to conventional treatment decreased recurrences and symptom persistence at 72 h. The efficacy of colchicine in addition to NSAIDs for acute pericarditis was shown by the ICAP trial.8 In this multicentre, double-blind study, adults with acute pericarditis were randomly assigned to receive either colchicine for 3 months or placebo, in addition to NSAIDs. The primary study outcome—incessant or recurrent pericarditis— occurred in 20 (16·7%) patients in the colchicine group versus 45 (37·5%) in the placebo group.8 Colchicine also significantly improved symptom persistence at 72 h, remissions at 1 week, the number of recurrences per patient, and number of admissions to hospital.8
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Colchicine for treatment of acute or recurrent pericarditis
Published Online March 30, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60113-6 See Articles page 2232
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