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Single-Pill Regimens for HIV-1 Infection To the Editor: With regard to the choice of a single-tablet combination regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection, an important consideration that is not highlighted in the article by Gandhi and Gandhi (July 17 issue)1 is the effect of the development of viral resistance to the chosen regimen on future treatment options. With a low real-world rate of adherence to antiretroviral medication of 55% (95% confidence interval, 49 to 62) in North America,2 treatment-associated drug resistance is a valid concern. The signature K103N mutation that develops with exposure to the single-tablet combination of efavirenz, tenofovir, and emtricitabine (EFV– TDF–FTC; Atripla, Bristol-Myers Squibb and Gilead Sciences) would not preclude the future use of rilpivirine with TDF–FTC (Complera, Gilead Sciences). However, the reverse is not the case, given the Y181C mutation that commonly occurs with exposure to the latter drug.3 Similarly, because the combination of dolutegravir, abacavir, and lamivudine (DTG–ABC–3TC) has superior virologic efficacy, has a high barrier to resistance, and retains activity against viruses that are resistant to the integrase inhibitors elvitegravir and raltegravir,4,5 some clinicians may consider reserving dolutegravir as a salvage drug for patients in whom treatment with other drugs in the class has failed. Onyema Ogbuagu, M.D. Arit Ogbuagu, M.D., M.P.H. Yale University School of Medicine New Haven, CT

[email protected] No potential conflict of interest relevant to this letter was reported. 1. Gandhi M, Gandhi RT. Single-pill combination regimens for

treatment of HIV-1 infection. N Engl J Med 2014;371:248-59. 2. Mills EJ, Nachega JB, Buchan I, et al. Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a metaanalysis. JAMA 2006;296:679-90. 3. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet 2011;378:238-46. 4. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elviteg­ ravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis 2014;210:354-62.


5. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus

raltegravir in antiretroviral-experienced, integrase-inhibitornaive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013;382: 700-8. DOI: 10.1056/NEJMc1410930

To the Editor: Gandhi and Gandhi delineate the public health precedents for HIV treatment with coformulated antiretroviral medications. In clinical practice, insurance vendors or public assistance programs often do not cover patented, coformulated medications. In addition, programs that cover the cost of antiretroviral therapy, hypertension, or diabetes often do not cover effective and reliable contraceptives. The need for contraception in HIV-positive women is of critical importance. Unintended pregnancy, complications of parturition, and HIV–AIDS are the leading causes of disability and death among women of reproductive age globally.1 The coformulation of a progestin-only contraceptive with an antiretroviral pill could address two urgent public health mandates. As compared with combined oral contraceptives, progestin-only pills require less restrictive screening, have wider distribution potential, and provide an additional safe contraception option for women with HIV infection.2 The design of a single-pill combination regimen with once-daily dosing that contains contraceptive and antiretroviral therapy could improve the lives of women around the world. Jessica M. Atrio, M.D. Kathryn Anastos, M.D. Albert Einstein College of Medicine Bronx, NY

[email protected] No potential conflict of interest relevant to this letter was reported. 1. Women and health: today’s evidence, tomorrow’s agenda.

Geneva: World Health Organization, 2009.

2. Atrio J, Stanczyk FZ, Neely M, Cherala G, Kovacs A, Mishell

DR Jr. Effect of protease inhibitors on steady-state pharmacokinetics of oral norethindrone contraception in HIV-infected women. J Acquir Immune Defic Syndr 2014;65:72-7. DOI: 10.1056/NEJMc1410930

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To the Editor: The clinical recommendation by Gandhi and Gandhi concludes that each of the anchor drugs in currently available single-pill combinations would be “suitable” to treat the patient in the case vignette. In my opinion, EFV– TDF–FTC may not be the most appropriate option for this patient, who has a history of depression, because a history of depression increases the risk of discontinuation of efavirenz1 and therefore subsequent treatment failure.2,3 Jean-Jacques Parienti, M.D., Ph.D. Centre Hospitalier Universitaire Côte de Nacre Caen, France

[email protected] Dr. Parienti reports receiving consulting, lecture, and grant support through his institution from ViiV Healthcare, Gilead Sciences, Bristol-Myers Squibb, Merck Sharp & Dohme, and Janssen Pharmaceuticals. No other potential conflict of interest relevant to this letter was reported. 1. Spire B, Carrieri P, Garzot M-A, L’henaff M, Obadia Y. Factors

associated with efavirenz discontinuation in a large communitybased sample of patients. AIDS Care 2004;16:558-64. 2. Parienti J-J, Massari V, Descamps D, et al. Predictors of virologic failure and resistance in HIV-infected patients treated with nevirapine- or efavirenz-based antiretroviral therapy. Clin Infect Dis 2004;38:1311-6. 3. Parienti J-J, Das-Douglas M, Massari V, et al. Not all missed doses are the same: sustained NNRTI treatment interruptions predict HIV rebound at low-to-moderate adherence levels. PLoS One 2008;3(7):e2783. DOI: 10.1056/NEJMc1410930

3TC combination pill was approved by the Food and Drug Administration1 [FDA] on August 22, 2014, after the publication of our article) so that clinicians can customize the regimen to the individual patient, rather than taking a one-sizefits-all approach. We agree with Ogbuagu and Ogbuagu that, in a patient in whom adherence is uncertain, one should certainly consider future treatment options; in that context, it may be best to initiate a regimen with a high genetic barrier to resistance, such as one containing either a protease inhibitor or, perhaps, dolutegravir. Atrio and Anastos raise the provocative idea of combining multiple antiretroviral medications with an oral contraceptive medication for HIVinfected women of reproductive age. The “poly­ pill” concept is gaining traction in the treatment and prevention of other diseases (e.g., cardiovascular disease) and was the topic of a recent FDA meeting.2 The challenge will be in designing such a pill and avoiding drug interactions, reduction in contraceptive or HIV-treatment efficacy, and toxic effects. We welcome additional exploration of this interesting and important concept. Parienti suggests that the single-pill combination of EFV–TDF–FTC should not be used in the patient in the clinical vignette because of his history of depression. We have found that most patients with mild depression are able to take this regimen without difficulty, but we agree with Parienti that, given recent concerns of an association between efavirenz and suicidality,3 other options may be preferable in patients who do not have well-controlled depression. Indeed, a growing number of clinicians are no longer using this regimen for initial therapy because of the availability of newer single-pill combination regimens that have fewer side effects, as summarized in our article.

The Authors Reply: Ogbuagu and Ogbuagu raise the important question of whether different antiretroviral regimens, including single-pill combinations, should be sequenced in a particular order. When multiple antiretroviral agents became available in the 1990s, clinicians sometimes chose an initial combination with subsequent regimens in mind in case the first therapy did not suppress viral replication. Now that virologic suppression can be maintained in most paMonica Gandhi, M.D., M.P.H. tients with good adherence to therapy, many of of California, San Francisco the concerns regarding regimen sequencing have University San Francisco, CA faded. Moreover, we have many more choices for second- and third-line regimens than in the past. Rajesh T. Gandhi, M.D. We recommend initiation of the most suitable Massachusetts General Hospital and safest regimen for a particular patient up Boston, MA front so that there is the best chance that durable [email protected] Since publication of their article, Dr. R.T. Gandhi reports that virologic suppression is maintained. Our article institution is receiving an educational grant from Gilead summarizes the pros and cons of the four avail- his Sciences and Roche for a project he is involved with. No further able single-pill combinations (the DTG–ABC– potential conflict of interest relevant to this letter was reported.

n engl j med 371;19 november 6, 2014


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1. Food and Drug Administration. Medication guide for Triumeq

( 205551s000lbl.pdf ). 2. Food and Drug Administration. September 10, 2014: Cardiovascular and Renal Drugs Advisory Committee meeting announcement ( ucm405489.htm).


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3. Mollan KR, Smurzynski M, Eron JJ, et al. Association be-

tween efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med 2014;161: 1-10. DOI: 10.1056/NEJMc1410930

Syndromes of Thrombotic Microangiopathy To the Editor: In their review of the thrombotic microangiopathy syndromes, George and Nester (Aug. 14 issue)1 do not mention the option of treating severe neurologic deficits in patients with shiga toxin–mediated hemolytic–uremic syndrome (ST-HUS) with IgG depletion through immunoadsorption.2 In the 2011 outbreak in northern Germany, the delay in the onset of neurologic symptoms (5 to 12 days after the onset of diarrhea; mean and median, 8.0 days) strongly suggested antibody involvement in the pathogenesis of these symptoms. Consequently, all 12 patients had substantial improvement, and 10 of them fully recovered after IgG depletion through immunoadsorption, despite the failure of all other known treatments. This treatment option, although based on one prospective, uncontrolled study, may be a lifesaving treatment and should be considered in similar cases.

plicates the binding of the Thomsen–Friedenreich antigen to preformed circulating IgM antibodies, owing to the neuraminidase-mediated cleavage of sialic acid residues from the membrane of glomerular capillary endothelial cells, red cells, and platelets.1 Neuraminidase-associated thrombotic microangiopathy is generally observed in pediatric patients with pneumonia and meningitis and rarely in those with isolated pneumococcal infection.2 The disease, frequently described as the hemolytic–uremic syndrome, has also been associated with group A beta-hemolytic streptococcus infection.3 Furthermore, the true incidence of neuraminidase-associated thrombotic microangiopathy could be underestimated.2 Pneumococcal infection should be included among the causes of the thrombotic microangiopathy syndromes and considered especially in pediatric patients.

Shraga Aviner, M.D., Ph.D. Haim Bibi, M.D.

Fabio Villa, M.D. Ente Ospedaliero Cantonale Bellinzona, Switzerland

Barzilai University Medical Center Ashkelon, Israel

[email protected]

[email protected] No potential conflict of interest relevant to this letter was reported. 1. George JN, Nester CM. Syndromes of thrombotic microangi-

opathy. N Engl J Med 2014;371:654-66. 2. Greinacher A, Friesecke S, Abel P, et al. Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial. Lancet 2011; 378:1166-73.

No potential conflict of interest relevant to this letter was reported. 1. Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangi-

opathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001;60:831-46. 2. Copelovitch L, Kaplan BS. Streptococcus pneumoniae–­ associated hemolytic uremic syndrome: classification and the emergence of serotype 19A. Pediatrics 2010;125(1):e174-e182. 3. Shepherd AB, Palmer AL, Bigler SA, Baliga R. Hemolytic uremic syndrome associated with group A beta-hemolytic streptococcus. Pediatr Nephrol 2003;18:949-51.

DOI: 10.1056/NEJMc1410951 DOI: 10.1056/NEJMc1410951

To the Editor: George and Nester mention the main causes and pathological and clinical features of the thrombotic microangiopathy syndromes, disorders that can also be associated with pneumococcal infection. The pathogenesis of this rare but severe complication probably im-


To the Editor: George and Nester describe cobalamin C deficiency as one underlying cause of thrombotic microangiopathies. On the basis of our experience with cobalamin C deficiency in these syndromes1 and the findings of other inves-

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Single-pill regimens for HIV-1 infection.

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