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Practice Changing UpDates
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Practice Changing UpDates
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Jul 13, 2017.

INTRODUCTION — This section highlights selected specific new recommendations and/or updates that we anticipate may change usual clinical practice. Practice Changing UpDates focus on changes that may have significant and broad impact on practice, and therefore do not represent all updates that affect practice. These Practice Changing UpDates, reflecting important changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.

ONCOLOGY (June 2017)

Management of a positive sentinel lymph node biopsy in patients with cutaneous melanoma

For patients with cutaneous melanoma and a positive sentinel lymph node biopsy, we suggest clinical observation and ultrasound surveillance of the positive nodal basin rather than immediate completion lymph node dissection (Grade 2B).

Historically, completion dissection of all involved nodal basins was considered the standard treatment approach for patients with cutaneous melanoma and a positive sentinel lymph node biopsy (SLNB). In the phase III Multicenter Selective Lymphadenectomy Trial II (MSLT II), patients with a positive SLNB were randomly assigned to either completion lymph node dissection or observation that included ultrasound evaluation of the appropriate lymph node basins at each follow-up visit [1]. Melanoma-specific survival at three years was the same for both groups, although the incidence of recurrence in regional lymph nodes was higher in patients managed with observation and ultrasound surveillance. The incidence of lymphedema was higher in patients who underwent immediate lymph node dissection. For patients with a positive SLNB, we suggest clinical observation coupled with ultrasound surveillance of the positive nodal basin. Completion lymph node dissection is indicated if, in the absence of distant metastases, there is evidence of regional lymph node recurrence. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'Multicenter Selective Lymphadenectomy Trial II'.)

ONCOLOGY (June 2017)

Next-generation ALK-inhibitors in crizotinib-naive ALK-positive NSCLC

For patients with newly diagnosed ALK-positive NSCLC, we recommend alectinib as first-line treatment (Grade 1B). For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib.

For patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), crizotinib has been administered as frontline therapy. However, newer agents have shown promising efficacy in advanced ALK-positive NSCLC:

In a global trial of 303 patients randomly assigned to frontline crizotinib versus the next-generation inhibitor alectinib (ALEX), those receiving alectinib experienced a longer progression-free survival (PFS, not reached versus 11.1 months), with fewer toxicities, at a median follow-up of approximately 18 months [2]. These results are consistent with an earlier Japanese trial [3].

In a phase III trial of 376 patients comparing ceritinib, another next-generation ALK inhibitor, with pemetrexed and a platinum agent, ceritinib improved progression-free survival (17 versus 8 months) [4]. Ceritinib has not been compared with crizotinib in the frontline setting.

For patients with newly diagnosed, ALK-positive NSCLC, we now recommend frontline therapy with alectinib. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

PULMONARY AND CRITICAL CARE MEDICINE (June 2017)

Revised follow-up for a solitary pulmonary nodule

For patients with a solid or subsolid (pure ground glass or part-solid) solitary pulmonary nodule (SPN) <6 mm, no routine follow-up is required. For patients with solid SPNs that have been stable over two years, or with subsolid SPNs that have been stable over five years on serial CT, we suggest no further diagnostic testing.

Fleischner Society guidelines have been updated to reflect the accumulating data on the malignancy risk of incidental pulmonary nodules and growth rates of lung cancer [5]. Important changes include guidance on identifying benign nodules with minimal follow-up imaging. For patients with a solid or subsolid (ground glass or part-solid) solitary pulmonary nodule measuring <6 mm, follow-up computed tomography (CT) is optional, but no longer required. A solitary pulmonary nodule that is solid and unchanged on serial CT over a two-year period, or subsolid and unchanged over a five-year period, is likely benign and does not need further diagnostic evaluation. Recommendations in UpToDate have been revised to reflect these new guidelines. (See "Diagnostic evaluation and management of the solitary pulmonary nodule", section on 'Management strategy' and "Diagnostic evaluation and management of the solitary pulmonary nodule", section on 'Solid nodules ≤8 mm'.)

OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (May 2017)

Tranexamic acid for management of postpartum hemorrhage

For women with postpartum hemorrhage diagnosed within three hours of delivery, we recommend administration of tranexamic acid as a component of overall treatment (Grade 1B). When more than three hours have elapsed since delivery, we still suggest tranexamic acid (Grade 2C), but the benefit of treatment is less clear.

Tranexamic acid, an antifibrinolytic drug, reduces bleeding in surgical and trauma patients. In a pragmatic randomized trial involving over 20,000 women with postpartum hemorrhage in over 20 countries (the World Maternal Antifibrinolytic Randomized Trial [WOMAN]), tranexamic acid, compared with placebo, reduced the relative risk of death due to bleeding by 20 to 30 percent, reduced the incidence of laparotomy to control bleeding, and was not associated with an increase in adverse effects [6]. Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage. (See "Postpartum hemorrhage: Medical and minimally invasive management".)

NEUROLOGY (May 2017)

Edaravone for amyotrophic lateral sclerosis

For patients with ALS who have a disease duration of two years or less, are living independently, and have an FVC ≥80 percent, we suggest treatment with edaravone (Grade 2B). We also suggest edaravone for patients with more advanced ALS (Grade 2C).

Edaravone is a free radical scavenger that is thought to reduce oxidative stress, which has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone may slow functional deterioration in some patients with ALS. An earlier trial found no benefit for edaravone compared with placebo, but a post-hoc analysis showed a possible treatment effect in a subgroup of individuals with early-stage ALS. A subsequent trial enrolled 137 Japanese patients within two years of ALS diagnosis who were living independently and had a forced vital capacity (FVC) of ≥80 percent [7]. Compared with placebo, functional decline at 24 weeks was smaller in the edaravone group, and the difference was considered clinically meaningful. Edaravone was approved in 2015 for the treatment of ALS in Japan and Korea and has now received regulatory approval to treat patients with ALS in the United States [8]. We now suggest edaravone for patients with early-stage disease as well as for those with more advanced disease, although the data are less compelling for the latter group. (See "Disease modifying treatment of amyotrophic lateral sclerosis", section on 'Edaravone'.)

HEMATOLOGY (May 2017)

Eltrombopag for adults with acquired severe aplastic anemia unable to undergo HCT

For adults with acquired severe aplastic anemia who are not candidates for allogeneic hematopoietic cell transplantation, we suggest eltrombopag plus standard immunosuppressive therapy (IST) rather than IST alone (Grade 2C).

Acquired aplastic anemia (AA) has a high morbidity, and allogeneic hematopoietic cell transplantation (HCT) is suggested as therapy for patients healthy enough to tolerate HCT who have a suitable donor. Immunosuppressive therapy (IST) is offered to those for whom HCT is not an option but is often ineffective in improving outcomes over the long term. A prospective cohort study in adults with acquired severe AA evaluated the effectiveness of IST plus eltrombopag, a thrombopoietin receptor agonist that acts on platelet precursors and hematopoietic stem cells [9]. Eltrombopag plus IST produced higher rates of overall hematologic response at six months compared with responses in a historical cohort (80 to 94 percent versus 66 percent for the historical group). Based on these findings, we now suggest administration of eltrombopag plus IST for individuals with acquired severe AA who are not candidates for allogeneic HCT. (See "Treatment of aplastic anemia in adults", section on 'Evidence for efficacy'.)

NEUROLOGY (April 2017)

Ocrelizumab for primary progressive multiple sclerosis

For patients with primary progressive multiple sclerosis, we suggest treatment with ocrelizumab (Grade 2B).

Ocrelizumab is the first drug to reduce the risk of disability progression among patients with primary progressive multiple sclerosis (PPMS), as shown by the multicenter ORATORIO randomized trial [10]. Compared with placebo, ocrelizumab modestly reduced the proportion of patients with disability progression at 24 weeks (30 versus 36 percent). In addition, ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk and led to improvements on other endpoints. While the long-term risks of infection and neoplasm with ocrelizumab are uncertain, there are no other disease-modifying therapies for PPMS. Therefore, we suggest treatment with ocrelizumab for most patients with PPMS. Ocrelizumab has also been approved by the US Food and Drug Administration for use in relapsing-remitting MS (RRMS), although its role in the early treatment of this form of the disease remains to be determined. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)

ONCOLOGY (March 2017)

Scalp hypothermia to prevent chemotherapy-induced alopecia

For women with breast cancer who are receiving chemotherapy that is expected to result in significant alopecia, and who place a high value on avoiding chemotherapy-induced alopecia, we suggest the use of a scalp cooling device (Grade 2A). Scalp hypothermia could also be discussed as a potential option for patients with other solid tumors who are receiving chemotherapy that is expected to result in significant alopecia, although the evidence base is less robust.

Two prospective studies have evaluated the efficacy of two different automated scalp cooling devices in women with early stage breast cancer [11,12]:

In an interim analysis of a randomized trial comparing the Paxman Scalp Cooling device and no scalp hypothermia for women with breast cancer receiving adjuvant chemotherapy (one-third anthracycline-based, the remainder taxane-based), one-half of the hypothermia group had limited hair loss (to less than 50 percent, not requiring a wig) compared with none in the control group [11]. Adverse events were all grade 1 and 2, including primarily headache and feeling cold. The success rate was higher with taxane-containing regimens.

In a multicenter prospective cohort study, 101 patients receiving non-anthracycline taxane-based chemotherapy and who used the DigniCap Scalp Cooling device were compared with 16 concurrently treated controls who did not use the device [12]. Two-thirds of the intervention group, compared with none of the control group, had limited hair loss (to less than 50 percent) one month after the end of chemotherapy. At a median follow-up of 2.5 years, no patient developed scalp metastases.

These results confirm prior studies on the efficacy and safety of scalp hypothermia to reduce chemotherapy-related hair loss. The FDA approved one device (DigniCap) for patients with breast cancer in December 2015 and expanded the approval to cover all solid tumors in July 2017. (See "Chemotherapy-induced alopecia", section on 'Efficacy and safety'.)

ALLERGY AND IMMUNOLOGY (February 2017)

Immunotherapy for stinging insect hypersensitivity in adults

We suggest not giving venom immunotherapy (VIT) to patients with reactions to stinging insects limited to cutaneous systemic symptoms and not involving other organ systems (Grade 2C). However, VIT is effective in reducing the severity of future reactions and may still be offered in selected situations.

Venom immunotherapy (VIT) for the treatment of patients with anaphylactic reactions to stings of Hymenoptera insects (eg, bees, yellow jackets, wasps, hornets, and fire ants) is highly effective in preventing future anaphylactic reactions. However, in an updated practice parameter from the American Joint Task Force, VIT is no longer suggested for adults with systemic reactions limited to the skin (ie, generalized erythema, pruritus, urticaria, or angioedema) as studies suggest these patients are at low risk for serious future systemic reactions [13]. This change brings the American approach into closer alignment with guidelines of other countries and is similar to the existing recommendation for children. Despite this revision, VIT may be appropriate for certain adults with cutaneous systemic reactions (eg, those with underlying medical conditions or medications that could affect the outcome of a systemic reaction, frequent unavoidable exposure to Hymenoptera, or impaired quality of life due to fear of future stings). (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients with past cutaneous systemic reactions'.)

INFECTIOUS DISEASES (December 2016)

Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection

For most patients with chronic HBV infection who initiate therapy with tenofovir, we recommend tenofovir alafenamide rather than tenofovir disoproxil fumarate (tenofovir DF) (Grade 1B). We also suggest that those initially started on tenofovir DF switch to tenofovir alafenamide (Grade 2B).

Tenofovir disoproxil fumarate is a first-line therapy for chronic hepatitis B virus (HBV) infection. A newer formulation of tenofovir, tenofovir alafenamide, was approved by the US Food and Drug Administration in November 2016 for the treatment of chronic HBV in patients with compensated liver disease [14]. In two large randomized noninferiority trials among patients with chronic HBV infection (both treatment-naive and experienced, and including patients positive or negative for HBV e antigen), tenofovir alafenamide resulted in similar rates of HBV suppression and fewer adverse effects on renal function and bone density at 48 weeks compared with tenofovir disoproxil fumarate [15,16]. Given these findings, tenofovir alafenamide is our preferred formulation for patients with chronic HBV who initiate therapy with tenofovir. We also favor switching those initially started on tenofovir disoproxil fumarate to tenofovir alafenamide. Given limited available safety data, we do not currently use tenofovir alafenamide in pregnant women. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogues'.)

INFECTIOUS DISEASES, PEDIATRICS, ADULT PRIMARY CARE, FAMILY MEDICINE (November 2016)

Meningococcal conjugate vaccination for HIV-infected patients

For all HIV-infected individuals older than two months, we suggest meningococcal conjugate vaccination (Menactra or Menveo) (Grade 2C).

Growing evidence has suggested that HIV-infected individuals have a disproportionate incidence of invasive meningococcal disease, with an estimated risk 5 to 13 times that of the general population. Because of this, the Centers for Disease Control and Prevention in the United States now recommends meningococcal conjugate vaccination (with MenACWY-CRM [Menveo] or MenACWY-D [Menactra]) for all HIV-infected individuals older than two months [17]. This includes a primary vaccine series for those who have not previously received it and interval booster doses every several years; the precise schedule depends on the age of the patient (table 1). Individuals may also have separate indications for serogroup B meningococcal vaccination. Evidence of vaccine efficacy in HIV-infected patients is limited to immunologic outcomes. (See "Immunizations in HIV-infected patients", section on 'Meningococcal vaccine' and "Meningococcal vaccines".)

INFECTIOUS DISEASES (November 2016)

HPV vaccine dosing for individuals younger than 15 years

For individuals younger than 15 years, we advise administration of human papillomavirus (HPV) vaccine in two doses separated by six months. Those 15 years and older should continue to receive a three-dose vaccine series.

For individuals younger than 15 years receiving human papillomavirus (HPV) vaccination, two vaccine doses administered at least six months apart are now recommended by the Centers for Disease Control and Prevention in the United States [18]. This new vaccine schedule is similar to schedules used in other countries and is supported by data demonstrating that two vaccine doses in young females have similar immunogenicity to three doses. However, the efficacy of fewer than three doses for prevention of cervical neoplastic disease has not been directly established. Three doses are still recommended for individuals older than 15 years because they have lower immunologic responses to HPV vaccination. (See "Human papillomavirus vaccination".)

HEMATOLOGY (October 2016, Modified October 2016)

Daratumumab-based regimens in relapsed multiple myeloma

Subject to availability, we recommend a daratumumab-based regimen for the treatment of first relapse in myeloma (Grade 1B).

Two recent multicenter randomized trials including over 1000 patients have demonstrated large improvements in progression-free survival (PFS) when the anti-CD38 monoclonal antibody daratumumab is added to standard regimens in relapsed multiple myeloma. The addition of daratumumab to either lenalidomide plus dexamethasone (POLLUX trial) or to bortezomib plus dexamethasone (CASTOR trial) resulted in substantially improved response rates and PFS with a mild to moderate increase in toxicity [19,20]. Mostly mild infusion reactions were common with the first infusion, but rarely resulted in drug discontinuation. Overall survival data are not yet mature. Based on these results we now recommend a daratumumab-based regimen for the treatment of first relapse in myeloma. (See "Treatment of relapsed or refractory multiple myeloma", section on 'Daratumumab'.)

PULMONARY AND CRITICAL CARE MEDICINE (October 2016)

Mycophenolate mofetil for scleroderma lung disease

For patients with systemic sclerosis who have respiratory symptoms, abnormal and/or declining pulmonary function, imaging evidence of interstitial lung disease, and no active infection, we suggest initiating treatment with mycophenolate mofetil (MMF) (Grade 2B).

Cyclophosphamide has been the suggested treatment for moderate-to-severe interstitial lung disease complicating systemic sclerosis (SSc-ILD) but has well-known toxicity. A recent randomized trial compared mycophenolate mofetil (MMF) with oral cyclophosphamide in 142 patients with SSc-ILD, exertional dyspnea, and features of progressive disease [21]. Pulmonary function and dyspnea improved in both groups, without a significant difference between groups. MMF was better tolerated than cyclophosphamide based on a longer time to patient withdrawal and lower incidence of leukopenia and thrombocytopenia. We now suggest initiating treatment for symptomatic progressive SSc-ILD with mycophenolate, rather than cyclophosphamide, due to comparable efficacy, better safety profile, and the option for longer-term therapy. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of an agent'.)

ONCOLOGY (October 2016)

Pembrolizumab in treatment-naïve advanced non-small cell lung cancer

For patients with treatment-naïve advanced non-small cell lung cancer that lacks EGFR or ALK genetic aberrations and expresses PD-L1 in at least 50 percent of tumor cells, we recommend pembrolizumab for initial therapy (Grade 1B).

Immunotherapy for patients with advanced non-small cell lung cancer (NSCLC) that lacks a driver mutation has shown promising results in the frontline setting:

In a phase III trial enrolling over 300 such patients whose tumors expressed programmed death ligand 1 (PD-L1) on at least 50 percent of tumor cells, pembrolizumab monotherapy improved progression-free survival, overall survival, and objective response rate compared with standard platinum-doublet chemotherapy [22]. It was also associated with lower treatment-related adverse effects.

In a randomized phase II trial of 123 patients with PD-L1 unselected advanced nonsquamous NSCLC, the addition of pembrolizumab to carboplatin and pemetrexed improved objective response rate (55 versus 29 percent, respectively) and progression-free survival (13 versus 6 months, respectively) relative to chemotherapy alone [23].

These data have led to approval by the US Food and Drug Administration (FDA) of pembrolizumab in the frontline setting for patients with advanced NSCLC lacking a driver mutation as monotherapy if PD-L1 is expressed on at least 50 percent of cells. More recently it has been approved in nonsquamous advanced NSCLC, in combination with carboplatin and pemetrexed, irrespective of PD-L1 levels. This regimen has not been compared, however, with platinum-based combinations incorporating concurrent and maintenance bevacizumab, which remains another option for such patients. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)

ONCOLOGY, PALLIATIVE CARE (August 2016)

Olanzapine for prevention of nausea and vomiting induced by highly emetogenic chemotherapy regimens

For patients receiving cisplatin and other highly emetogenic chemotherapy regimens, we suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy (a combination of a 5-HT3 receptor antagonist, dexamethasone, and an NK1R antagonist) (Grade 2B).

The antipsychotic olanzapine may be a particularly useful agent for preventing delayed chemotherapy-induced nausea and vomiting, which is often poorly controlled with conventional antiemetics. The effectiveness of adding olanzapine to a standard antiemetic regimen was shown in a trial in which 380 patients receiving highly emetogenic chemotherapy (cisplatin or doxorubicin/cyclophosphamide for breast cancer) were randomly assigned to dexamethasone, an NK1R antagonist, and a 5-HT3 receptor antagonist plus either olanzapine (10 mg daily orally on days 1 through 4) or placebo [24]. The proportion of patients with no chemotherapy-induced nausea (the primary endpoint) was higher with olanzapine both in the first 24 hours after chemotherapy and in the delayed period. Rates of complete response (no emesis and no use of rescue medication) were also higher with olanzapine over a five-day period. Patients receiving olanzapine had more sedation on day 2 (severe in 5 percent), which resolved despite continued olanzapine. On the basis of this trial, we now suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy for patients receiving highly emetogenic chemotherapy. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Olanzapine'.)

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REFERENCES

  1. Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 2017; 376:2211.
  2. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017.
  3. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017; 390:29.
  4. De Castro Jr G, Tan DS, Crino L, et al. First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4). WCLC 2016; PL03.07.
  5. MacMahon H, Naidich DP, Goo JM, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017; 284:228.
  6. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017.
  7. Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017; 16:505.
  8. FDA approves drug to treat ALS. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm557102.htm (Accessed on May 09, 2017).
  9. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med 2017; 376:1540.
  10. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 2017; 376:209.
  11. Nangia J, Wang T, Osborne C, et al. Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial. JAMA 2017; 317:596.
  12. Rugo HS, Klein P, Melin SA, et al. Association Between Use of a Scalp Cooling Device and Alopecia After Chemotherapy for Breast Cancer. JAMA 2017; 317:606.
  13. Golden DB, Demain J, Freeman T, et al. Stinging insect hypersensitivity: A practice parameter update 2016. Ann Allergy Asthma Immunol 2017; 118:28.
  14. U.S. Food and Drug Administration Approves Gilead’s Vemlidy (Tenofovir Alafenamide) for the Treatment of Chronic Hepatitis B Virus Infection. http://www.gilead.com/news/press-releases/2016/11/us-food-and-drug-administration-approves-gileads-vemlidy-tenofovir-alafenamide-for-the-treatment-of-chronic-hepatitis-b-virus-infection (Accessed on November 28, 2016).
  15. Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1:185.
  16. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1:196.
  17. MacNeil JR, Rubin LG, Patton M, et al. Recommendations for Use of Meningococcal Conjugate Vaccines in HIV-Infected Persons - Advisory Committee on Immunization Practices, 2016. MMWR Morb Mortal Wkly Rep 2016; 65:1189.
  18. CDC recommends only two HPV shots for younger adolescents, October 19, 2016. https://www.cdc.gov/media/releases/2016/p1020-hpv-shots.html (Accessed on October 22, 2016).
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