ANTIRETROVIRAL AGENTS,Nucleosidic reverse transcriptase inhibitors
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",isbn:"978-1-83969-234-5",printIsbn:"978-1-83969-233-8",pdfIsbn:"978-1-83969-235-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"a5f5277a1c0616ce6b35f4b44a4cac7a",bookSignature:"Dr. Basel I. Ismail",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10013.jpg",keywords:"Thermodynamics, Heat Transfer Analyses, Geothermal Power Generation, Economics, Geothermal Systems, Geothermal Heat Pump, Green Energy Buildings, Exploration Methods, Geologic Fundamentals, Geotechnical, Geothermal System Materials, Sustainability",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 29th 2020",dateEndSecondStepPublish:"November 26th 2020",dateEndThirdStepPublish:"January 25th 2021",dateEndFourthStepPublish:"April 15th 2021",dateEndFifthStepPublish:"June 14th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Leading research investigator in a collaborative project (2007-2010) with Goldcorp-Musselwhite Canada Ltd. and Engineering of Lakehead University, owner of a Ph.D. degree in Mechanical Engineering from McMaster University, Hamilton, Ontario, Canada and postdoctoral researcher (2004 to 2005) at McMaster University.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"62122",title:"Dr.",name:"Basel",middleName:"I.",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail",profilePictureURL:"https://mts.intechopen.com/storage/users/62122/images/system/62122.jpg",biography:"Dr. B. Ismail is currently an Associate Professor and Chairman of the Department of Mechanical Engineering, Lakehead University, Thunder Bay, Ontario, Canada. In 2004, Prof. Ismail earned his Ph.D. degree in Mechanical Engineering from McMaster University, Hamilton, Ontario, Canada. From 2004 to 2005, he worked as a Postdoctoral researcher at McMaster University. His specialty is in engineering heat transfer, engineering thermodynamics, and energy conversion and storage engineering. Dr. Ismail’s research activities are theoretical and applied in nature. Currently, his research areas of interest are focused on green engineering technologies related to alternative and renewable energy systems for power generation, heating and cooling. Dr. Ismail was the leading research investigator in a collaborative project (2007-2010) with Goldcorp-Musselwhite Canada Ltd. and Engineering of Lakehead University. This innovative project was state-of-the-art in geothermal heat pump technology applied in Northwestern Ontario, Canada. Dr. Ismail has published many technical reports and articles related to his research areas in reputable International Journals and Conferences. During his research activities, Dr. Ismail has supervised and trained many graduate students and senior undergraduate students in Mechanical Engineering with projects and theses related to innovative renewable and alternative energy engineering, and technologies.",institutionString:"Lakehead University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Lakehead University",institutionURL:null,country:{name:"Canada"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"184402",firstName:"Romina",lastName:"Rovan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/184402/images/4747_n.jpg",email:"romina.r@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"5084",title:"Advances in Geothermal Energy",subtitle:null,isOpenForSubmission:!1,hash:"d4647f1f9dae170acf327283d55abbf1",slug:"advances-in-geothermal-energy",bookSignature:"Basel I. Ismail",coverURL:"https://cdn.intechopen.com/books/images_new/5084.jpg",editedByType:"Edited by",editors:[{id:"62122",title:"Dr.",name:"Basel",surname:"Ismail",slug:"basel-ismail",fullName:"Basel Ismail"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5602",title:"Renewable Hydropower Technologies",subtitle:null,isOpenForSubmission:!1,hash:"15ea891d96b6c9f2d3f28d5a21c09203",slug:"renewable-hydropower-technologies",bookSignature:"Basel I. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"40955",title:"HIV/AIDS: Vertical Transmission",doi:"10.5772/53204",slug:"hiv-aids-vertical-transmission",body:'\n\t\tIn The Eight Millennium Development Goals, the World Health Organization proposed to attempt at reverting the world negative HIV/AIDS epidemics through disease prevention and treatment for the year 2015. Attaining virtual elimination of Vertical Transmission (Prevention of mother-to-child transmission, PMTCT) worldwide is one of such aims [1].
\n\t\t\tThe current chapter will address topics related to epidemiologic, pathophysiological, diagnostic and therapeutic aspects of vertical transmission of the Human Immunodeficiency Virus (HIV). Such information will enable the reader to understand how the health strategies aiming at preventing transmission to the fetus have turned into a paradigm of Perinatal Medicine, since the implementation of a series of biomedical interventions has proven to be successful to prevent transmission of HIV from an infected pregnant mother to her child.
\n\t\tWorld Epidemiological Status
\n\t\t\tPrevalence of Vertical Transmission (VT) in the different regions of the world varies with geographic location and, specifically, with the economic resources invested by the different countries to support various strategies applied to health care policies that aim at the prevention and treatment of infected mothers. Proof of thereof is the fact that in countries with government programs in which the economic support is sufficient to implement the planned strategies for VT prevention, the prevalence of perinatal infection is under 2% [2,3].
\n\t\t\tHIV epidemics are showing a trend towards stabilization worldwide. Thus, in 2009 approximately 2.6 million persons became newly infected by the virus, representing 19% fewer than the newly infected in 1999 and more than a fifth less (21%) of the estimates in 1997. In fact, in 33 countries the incidence of infection has fallen by 25%. This includes 22 countries of the Sub-Saharan African region, the zone with the highest number of new cases worldwide (Ethiopia, Nigeria, South Africa, Zambia and Zimbabwe). In Eastern, Central and Western Europe, Central and Northern Asia the incidence of HIV infection has remained stable for the past five years. However in some high income countries infection rates have increased due to sex practices between homosexuals. Central Asia and Eastern Europe continue with high transmission rates among drug addicts and their sexual partners [4].
\n\t\t\tRegarding vertical transmission, an estimate of 370,000 children became infected with HIV during perinatal and lactation periods in 2009. Such figure is quite lower than the estimated 500,000 newly infected children in 2001. The latter has been possible thanks to Vertical Transmission (VT) prevention healthcare strategies that have been planned and implemented. Accordingly, the WHO and the UNAIDS proposed to virtually eliminate such transmission route by 2015. To accomplish such goal, besides the efforts already implemented, they stated the importance of controlling the infection among youngsters. It is estimated that more than half of seropositive persons are girls and women [1,4].
\n\t\t\tIn the Sub-Saharan African region, there are 8 times more infected women than men among persons aged between 15 and 24. Most of women are infected during unsafe heterosexual sexual activity. Such situation is the main responsible for the fact that such countries are assembling 90% of the children infected worldwide. Despite of the latter, the incidence of subjects with a carrier status among children under 15 years of age has declined in 32% in South Africa, the country in which AIDS is the main cause of maternal death and that accounts for 35% of deaths in children under 5 years of age. Accordingly, worldwide data show that only 15% of women in whom the carrier status had been detected during their perinatal period stayed subsequently on lifelong antiretroviral therapy [4].
\n\t\t\tIt is estimated that approximately 4.9 million people in Asia were seropositive during 2009. Such figure is similar to those reported in the previous years, thus reflecting that the epidemics has stabilized. In such continent, the number of infected children under the age of 15 has increased marginally, from 140,000 in 2005 to 160,000 in 2009 and AIDS-related deaths have dropped in 15% since 2004 [4].
\n\t\t\tIn Western Europe, epidemiology indicators regarding maternal carrier status have evolved favorably. The estimated prevalence of infection among pregnant women in the United Kingdom is 0.2% and HIV screening coverage in gestating women is 90%. The latter has resulted in a sustained decline of VT from 12% in 1999 to 2% in 2007 [4,5].
\n\t\t\tIn North America the carrier status has reached stability and VT has evidenced a dramatic decrease. In Canada, infection of the newborn has decreased from 5.2% in 1997 to 2.7% in 2012, and when the seropositive mother was administered HAART, such figure reached 0.4% [4,6].
\n\t\t\tIn Central and South America the number of affected children under 15 years of age is still low, with approximately 4000 new cases during 2009, in spite of the fact that the coverage of VT prevention programs is only marginally superior to that reported in countries with low or moderate income [4].
\n\t\t\tAccording to reports from 2006, the estimated number of seropositive subjects in Latin America is 1.7 millions, with 140,000 new cases and 65,000 deaths. Two thirds of the infected individuals live in four countries: Argentina, Brazil, Colombia and Mexico. The main agent responsible for the infection is HIV-1. The most commonly isolated genotype is type B, followed by types F and A [2].
\n\t\t\tIn the American countries that compose the Southern Cone, HIV/AIDS epidemiological surveillance is carried out through mandatory notification (passive mechanism) and in some, through active surveillance by means of sentinel centers [2].
\n\t\t\tMost of such Latin American countries have implemented, since the second half of the 90s, an Antenatal Prevention of Mother To Child Transmission (APMTCT) program, consisting of the early voluntary diagnosis of HIV infection in the gestating population, universal access to antiretroviral therapy (ART) for the mother-child binomial, the C-section surgery and suppression of lactation, a program that aims at eliminating vertical transmission as a route of infection [2,3].
\n\t\t\tThe main route of transmission in Latin America is represented by sex between men. There has been a significant increase in transmission through heterosexual intercourse since 1990. With the exception of Argentina, where initially transmission was mainly represented by needle sharing during drug injection, with a current dramatic drop, estimates of new cases of transmission through such route in 2005 do not exceed 5%. On the other hand, there is concern in the area, regarding the relationship between HIV and drug addition, since it has been demonstrated that illicit drug abuse, regardless of the route of administration, favors risk behaviors [2].
\n\t\t\tIn view of the above stated, it is possible to conclude that the features of the epidemics in the Southern Cone have varied, showing a trend to impoverishment, feminization, and shift towards homosexual and scholar populations. Moreover, the fact of the most affected age group is between 20 and 39 years is of great importance, since it demonstrates that the mostly affected population is that representing the childbearing age, a situation that has a direct impact on VT risk. The latter warrants the importance of implementing human sexuality education to all levels of the population, providing the necessary information and recognizing the right of women to be informed to enable them to take the appropriate measures to protect themselves and prevent HIV infection. [2-4].
\n\t\t\tThe rate of HIV seropositive pregnant women fluctuates in the different countries of the Region, between 3 and 7/1000. It is estimated that more than 2 million HIV (+) women get pregnant and 90% of them belong to developing countries, thus between 370,000 and 500,000 infected children are born annually, that die mostly because of the disease [4]. Pregnancy would play a protective role for maternal mortality among HIV (+) women. Such effect would be related to the low pregnancy rates achieved among women at advanced stages of the disease. [2]. Conversely, in developed countries, the rate of maternal mortality has decreased significantly since the introduction of the Highly Active Antiretroviral Therapy (HAART). Moreover, the latter has increased the probability of achieving pregnancy, thus decreasing the rate of stillbirths and gestation-related diseases [7].
\n\t\t\tSince the beginning of the pandemics, the importance of VT as transmission route has been clear. However, not even the most optimistic would have thought that PMTCT would turn into an example of effective biomedical intervention to prevent HIV transmission. It is important to point that most of Latin American countries have healthcare programs aiming at decreasing VT (PMTCT) that are based on the early prenatal voluntary screening for infection, the offering of antiretroviral therapies (ARVT), the C-section [8], substitution of breastfeeding [9] and multidisciplinary management during pregnancy. Regarding antenatal carrier status diagnosis, it is important to note that there are studies that reveal that between 25 and 55% of the total number of pregnant women who accept the test do not schedule a subsequent visit to know the results, thus they do not receive therapy. The latter suggests that fast intrapartum tests should be implemented on pregnant women unaware of their serologic condition. This is supported by a recent study carried out in Peru. The study concluded that the use of fast result tests (oral or blood) is a strategy advisable to decrease VT risk, in populations where PMTCT coverage does not reach the expected goals [10].
\n\t\t\tPharmacological measures that have been implemented to decrease VT in the Southern region of America, were based on the ACTG 076 protocol [11] involving therapeutic antiretroviral management aiming at obtaining low or undetectable maternal viral loads, without toxic and/or teratogenic fetal effects. Such protocol consisted on the administration of Zidovudine to the mother during pregnancy and delivery, as well as to the newborn until the 6th week of life, together with indication of an elective C-section operation and contraindication of breastfeeding. Such scheme managed to decrease VT in the region, from 29% to 5.6% during 2001. [2] Subsequently, due to the emergence of new evidence supporting that triple-drug therapy was even more effective than monotherapy for VT prevention, a protocol was designed using a combination of reverse transcriptase and protease inhibitors. Such schemes were named together HAART. Thanks to such therapy, VT has dropped to figures close to 1% [2].
\n\t\t\tBecause of the implementation and coverage of healthcare government programs in countries of the region, only few pregnant women have viral loads higher than 1000 copies/ml in the proximity of delivery. The latter is responsible for the VT drop estimated as 1%. [2] A recent study assessed the risk of VT in pregnant women who were administered PMTCT and concluded that the VT risk was 0.097 (95% IC; 0.030-0.163). This reflects a reduction of transmission risk related to such route in almost 40% regarding VT before the implementation of such program [12].
\n\t\t\tChile, where an early detection program and timely treatment are currently being carried out, is probably one of the countries in the region having reached the best VT rates. This is a result of healthcare strategies aiming an adequate and permanently updated diagnosis of the behavior of the epidemics in the country. The proportion of female HIV carriers has increased as compared to that of males, due to the fact that the main transmission route is sex (93.6%). Such figure together with the impact of viral transmission both through homosexual as well as bisexual intercourse (46.1%), positions the monogamous heterosexual woman as the highest risk population (51.1%). Moreover, there is a sustained increase of cases transmitted through sex between men and women as compared to those transmitted through homosexual intercourse. This has shifted the epidemics towards heterosexual population groups, with a higher impact among female populations [2,3].
\n\t\t\tTo summarize, HIV VT in the region is responsible for a low percentage of people reported with HIV/AIDS, but is accountable for most of the children affected by the infection in the Southern Cone. An important reduction of transmission by means of such exposition route, reaching levels very close to the proposed goals, has been evidenced. Such decline might probably be explained by the wide coverage and effectiveness of the measures propounded by the health authorities to tackle the issue [2,3].
\n\t\tThe Human Immunodeficiency Virus (HIV) is a lentivirus that belongs to the Retroviridae family. Two types of HIV have been identified: HIV-1, the most common, results in acquired immunodeficiency syndrome and death, and HIV-2, affecting mainly inhabitants or visitors from Western Africa, is transmitted less effectively and results in a more indolent disease with subsequent AIDS and death. They share less than 50% sequence homology. Through phylogenetic analysis, HIV-1 strains can be divided into two large groups: The M (Major) group in turn divided into 10 subtypes (from A to J) and the O (Outlier) group. The eventual importance of HIV-1 typification lies in developing antibody screening techniques, diagnosing the infection in the newborn, and in the quantification of plasma viral RNA for follow up of infected patients [13, 14,15].
\n\t\t\tThis monostranded RNA virus incorporates its genetic material into the host cell DNA, infecting cells that express CD4 antigen on their surface, such as helper T cells, macrophages, central nervous system cells and even placental cells [13,16,17].
\n\t\t\tOnce the infection has occurred, the patient may present a primoinfection characterized by mononucleosis–like non-specific symptoms, where antibody production is triggered. Subsequently the patient undergoes a silent carrier phase. The latter used to last between 9 and 11 years before the emergence of antiretroviral therapy. As the immune system is being progressively involved, the host becomes more susceptible to suffer opportunistic infections, cancers and dementia / encephalopathy, which are complications that enable labeling such stage as AIDS stage. In further consensus, the following findings were added: CD4 count under 200/mm3, uterine cervix cancer, lung tuberculosis and recurrent pneumonia [13,16,17].
\n\t\tThe genome of HIV-1 is relatively small, and composed of genes coding for structural, regulatory and accessory proteins. The viral particle joins the cells of the susceptible host, among which are T cells, monocytes, macrophages, follicular dendritic cells and microglial cells. A high affinity bond is generated between the gp 120 of the viral surface and the CD4 receptor molecule on the host cell. Cell membranes fuse together and the virus enters the cell, uncovering its RNA. It is propounded that after infection, it is the downregulation of CD4 expression on the infected cell surface that prevents a superinfection, enables an efficacious replication of the virus, and decreases the possibility of early cell death or apoptosis. During an early stage, the viral reverse transcriptase is activated together with other factors, and complete double stranded DNA copies are formed from the viral RNA. Such DNA copy is transported to the cell nucleus and binds to the host cell DNA through the viral integrase, generating the so-called provirus. The provirus may remain latent during a period of time. The host factors that influence the latency period duration are unknown. In activated cells, proviral transcription generates genomic RNA for its incorporation into new virions and messenger RNA that will be translated into structural proteins and several regulator and accessory proteins that facilitate viral replication, assembling and release [13,16,17].
\n\t\t\tThe adult immune system has several components that are critical for HIV infection, such as B and T cells, antigen-presenting cells, major histocompatibility antigens (types I and II), natural killer cells, cytokines and complement. Before an infection or antigenic stimulation, B cells are always “naïve”. Following their stimulation, they generate two HIV specific subgroups that actively secrete antibodies against the virus. Likewise, there are “innocent” and other T cells with specific memory as a result of a prior exposure to the virus. In the great majority of the infected people HIV invasion disrupts normal immune reactions and induces a chronic progressive, polymorphic dysfunction that, at a given time, makes the individual susceptible to opportunistic infections, cancers, neurological disorders and premature death. The initial HIV infection in adults is frequently followed 2 to 6 weeks later by an acute viral syndrome that manifests with fever, pharyngitis, myalgia, tender lymphadenopathies, non-specific rash and lasts from 7 to 14 days. There is an acute drop of circulating lymphocyte counts, with a fairly rapid normalization of figures. However, CD4+ T cell counts do not fully regain baseline values. During such period viral replication and dissemination to lymph nodes and mononuclear / macrophagic cells occur speedily [13,16,17].
\n\t\t\tThe circulating viral load is high in the initial absence of an effective antibody response. Typically, IgM appear one or two months after HIV exposure, followed by IgG (specifically anti-gp 120/41) and the development of an anti-p24 response that fades out in more advanced stages of the infection. Shortly afterwards, anti-gp120 and gp41 antibodies emerge, and persist for a lifetime. As anti–HIV antibody titers increase, the circulating viral load decreases and the infected subjects initiate an asymptomatic phase that commonly lasts from 3 to 11 years. During such asymptomatic phase viral replication is extremely intense, as well as is the destruction and replacement of CD4+ T cells. It should be taken into consideration that before causing a gradual CD4+ T cell depletion, HIV infection causes a CD4+ T cell dysfunction. Chemoprophylaxis, antibody-related cell-mediated cytotoxicity, intracellular antimicrobial activity and disorders of cytokine production also occur due to monocyte and macrophage dysfunction caused by the HIV infection [13,16,17].
\n\t\t\tDuring pregnancy, the mother undergoes a modulation of her immune response characterized by a TH2 response (humoral type) more prominent than TH1-type (cellular) response that renders her more susceptible to certain infections. Based on the latter, it has been postulated that pregnancy might influence the course of the infection. Such hypothesis has been thoroughly discussed, and currently the conclusion is that gestation does not have adverse effects on survival or on the expression of the disease. Such conclusion is supported by the fact that the absolute CD4 count and the viral load remain stable during pregnancy in untreated pregnant women [7,13,16 -18].
\n\t\t\tAlmost all clinical disorders described in HIV-infected adults may appear in infants, however their rates of onset might be different in both life periods. The evolution of disease among infants infected during the perinatal stage is faster than in adults. This has raised questions such as if the developing immune system in fetuses and newborns represents a better ground for viral replication or is less efficient for infection control. Immaturity of the immune system of fetuses, newborns and infants causes two pathophysiological differences between adults and children: B cells are seldom susceptible to HIV infection and their circulating values remain normal; however such cells show abnormalities in infected children as compared to infected adults. As the infant has been exposed to few external antigens (and thus has a limited immune memory), the resulting immune dysfunction is more severe than in adults. Because of the poor development of T and B cell memory, children infected in perinatal stages are more vulnerable to antibody-mediated pyogenic infections than infected adults [13,16,17].
\n\t\t\tAlmost as soon as the infected cells die, they are replaced, until the degree of the immune dysfunction is such as to make the immune control of the virus inefficient. Thus, the clinical conditions defining AIDS are progressively met.
\n\t\tThe main HIV transmission risk factor for females worldwide is sexual intercourse. More than 90% of HIV-AIDS-infected women have acquired the infection through heterosexual transmission. In most of the cases, such women had sexual intercourse only with their stable spouse, thus attesting for their vulnerability to transmission, which is directly related to their sexual partner’s behavior (bisexuality, drug addictions, promiscuity) [3].
\n\t\t\tThe reasons explaining why women are more susceptible to be infected by HIV than men are varied. Thus, healthcare staff must be aware of such factors and therefore generate a sympathetic and empathic environment to achieve a good physician-patient relationship. Among such reasons, the following should be considered:
\n\t\t\t- Sexual transmission of the virus is several times more common from men to women than vice versa. Women with thinned vaginal mucosa or lacking the physiological defense mechanisms (pubertal and postmenopausal women) are at higher risk.
- Asymptomatic sexually transmitted vaginosis is commonly underdiagnosed and results in a disturbance of the indemnity of the vaginal mucosa.
- Women depend economically, socially and emotionally on men and such situation makes rejection of high-risk sexual intercourse difficult.
- Cultural norms encourage promiscuity among males, thus increasing transmission risk among monogamous females.
- There is a lack of easy access to woman-controlled-preventive methods (female condoms).
Regarding the last point and aiming at identifying other prevention methods, recent studies have demonstrated that the use of tenofovir gel might be a useful tool to prevent infection. In fact, a South African study concluded that the pre and post-coital prophylactic use of such microbicide among women aged between 18 and 40 reduced HIV infection in 39% and HSV-2 infection in 51%. [19] On the other hand, circumcision in adults has proven to be effective to prevent infection among seronegative males with an HIV+ partner. The latter has led the UNAIDS and WHO to recommend such intervention in countries with high prevalence [4]. Finally, there are also studies that propose the use of tenofovir prior to sexual intercourse in infected or high-risk couples. All these prophylactic measures should be assessed with further adequately designed studies.
\n\t\t\tProbably due to such reasons and in light of the pooled data in developing and developed countries, the proportion of HIV carrier women has increased as compared to that of men. The cause is that the main transmission route is sex. The latter together with the impact of viral transmission route in homo and heterosexual mode, have transformed heterosexual monogamous women into the highest risk population. Moreover, there is a sustained increase of cases transmitted by sexual intercourse between men and women as compared to those transmitted through homosexual intercourse. This has shifted the epidemics towards population groups with a lower social-economic level and with a clear decrease of females in higher school education levels [2, 3, 16,17].
\n\t\t\tEpidemiology studies suggest that the observed prevalence among women in childbearing age is comparable to prevalence in pregnant women. On the other hand, pregnancy rates in seropositive women that have not developed AIDS are comparable to those seen among uninfected women, while among women who developed the disease the probability of getting pregnant is quite lower [13-15].
\n\t\tMost of women discover their carrier status or their disease during pregnancy or subsequently after birth upon screening of their offspring. With regard to the need for screening of all women during their pre and/or post-conception consultation, the American College of Obstetricians and Gynecologists recommends carrying it out on a routine basis, which is a conduct commonly adopted in many countries of the world. In fact, in most of these countries, such screening is performed together with the mandatory pre-test counseling act, with the informed consent and with the willfulness of individuals in the decision to undergo the test. Therefore, screening requires the participation of staff trained in “counseling”, which has reinforced the decision to undergo the test among women. This has shown to be of most importance for the generation of awareness about the disease, adherence to therapy and the incorporation of behaviors by the carrier to prevent transmission to her personal environment [20-24]. Pre and post-conceptional counseling is understood as a “confidential dialogue between a questioner and a counselor aiming at empowering women to face stress, decision making regarding HIV/AIDS during pregnancy and discussion of the elements for prevention of vertical transmission”. It is important to recommend the following topics to be addressed upon counseling:
\n\t\t\t- Impact of HIV on pregnancy.
- Vertical Transmission risk and impact of prophylactic measures.
- Risks and benefits of antiretroviral therapy.
- Prognosis for children who become infected.
– Breastfeeding-related risks.
The most popular methods worldwide are tests that screen for specific antibodies against viral antigens. The most used technique for screening is Enzyme Linked Immunosorbent Assay (ELISA). The most used technique for infection confirmation is the Western blot technique [25].
\n\t\t\tThe ELISA test uses antigens derived from the intact virus and binds them to microtitration wells. The serum or plasma from the patient is added into the wells and if there are antibodies against HIV they bind to the antigen present. A chromogen substrate is also provided to evidence the potentially bound enzyme and the intensity of the color generated is read on a spectrophotometer. Color reading is proportional to the amount of the enzyme-antibody complex that bound the HIV antigen present in the wells. Commercially available tests have sensitivity and specificity rates between 98 and 100%. The disadvantage of such tests is they detect antibodies and thus may yield false positive results if transmission occurred shortly before the test. Such time lapse is known as window period, which may last between 3 and 6 months. For such reason, fourth generation ELISA is recommended. Such test is able to detect simultaneously Ag p24 and its respective antibodies, and therefore it can shorten the window period to approximately 30 days, with 99.9% sensitivity and 99.5% specificity. Despite the latter, it is important to point that the positive predictive value of this test during pregnancy is approximately 50%, because it is applied to a low prevalence population, and therefore a confirmation test is mandatory (Western blot) [16].
\n\t\t\tAdditionally, in pregnant women with unknown serology status and attending consultation for labor or medical situations where pregnancy termination is imminent, services should have rapid diagnostic techniques. Despite their non-optimal specificity and sensitivity, positive results on such tests should be able to generate the recommendation of preventive measures during the peripartum period, with prior patient informed consent [5,10].
\n\t\t\tThe confirmation Western blot technique is carried out with a nitrocellulose strip to which HIV shell proteins are added. Patient serum is applied on the strips: any antibody against such virus present in serum will bind to its specific antigen. This generates a series of dark bands. By comparing the band position with a control, it is possible to determine if the patient’s blood contains HIV-specific antibodies [16].
\n\t\t\tOn occasions, individuals with recent infection or in the process of structuring a complete antibody response yield undetermined responses. In such cases, the test should be repeated within one to two months.
\n\t\t\tPCR tests are sensitive and useful to confirm the infection status. They are able to detect very small amounts of virus and they do not rely on an antibody response to infection. PCR is used in clinical practice to establish the infection status on infants born to infected mothers and potentially within the window period between infection and presence of detectable specific antibodies. PCR and other amplification techniques have been improved to quantify HIV RNA. There is considerable interest on perfecting reliable tests to detect the virus in oral fluids or urine, since they are easy to collect without causing either disturbance to the patient or risks to the collector. Moreover, they can be especially helpful in children and adults in whom vein access can be difficult [16].
\n\t\t\tAssessment of HIV infection status is complex in children under the age of 6 months because of gestation and early lactation immunology. The most commonly used tests in adults are based on the detection of IgG antibodies against the virus. During pregnancy, maternal IgG crosses easily the placenta towards fetal circulation, where it remains until 18 months after birth. For such reason, assessment of the HIV infection status in infants requires testing other than ELISA and Western blot. The options are virus cultures and PCR, as well as detection of IgA antibodies directed against HIV [14,16].
\n\t\tAccording to epidemiological studies, pregnancy rates among seropositive women that have not presented AIDS are comparable to rates in uninfected women. The probability of becoming pregnant is quite lower among women who develop AIDS. Despite of certain contradictory evidence, latest studies seem to confirm that pregnancy does not affect the course or the complications of the disease [26].
\n\t\t\tAs for the role played by the viral load or the immune condition of the pregnant woman, there is evidence supporting a close relationship between high viral loads and higher VT risk. However there is not a viral load warranting a virus-free neonate. Mother-to-child transmission is possible despite viral levels being undetectable in the mother. On the other hand, maternal CD4 concentrations < 700 cells/mm relate to a higher VT risk [27].
\n\t\t\tNevertheless, opportunistic infections (Pneumocystis jirovecii, Herpes Zoster, etc.) and prevalent diseases such as tuberculosis and malaria are those with more aggressive course in seropositive pregnant women and increase significantly maternal and perinatal morbidity and mortality. [28]
\n\t\t\tVertical transmission is one of the mostly studied transmission routes, thus it is possible to share some conclusions regarding the moment of transmission to the fetus or newborn and the factors that increase VT risk [14,16].
\n\t\t\tMoment of transmission to the product of conception:
\n\t\t\t- During pregnancy: up to 35%.
- During delivery: up to 65%.
- During lactation: up to 14%.
Obstetric factors that favor VT:
\n\t\t\t- Premature Rupture of Membranes of more than 4 hours.
- Premature delivery.
- Low Birth Weight (under 2,500 g).
- Ovular infection.
- Direct contact of the fetus with cervical and vaginal secretions and/or blood in the birth canal.
Fortunately, the gravid status does not seem to have an impact on the course or the natural history of HIV infection, since although a decrease in CD4+ T cell counts has been described during pregnancy, they return to baseline values after delivery [17]. In the absence of complications such as drug addictions or chronic medical diseases, the incidence of obstetric pathology does not increase; spontaneous abortion, intrauterine growth restriction, preterm delivery and stillbirth are within the expected prevalence range. However, the risk of infectious complications increases among pregnant women with a significant impairment of the immune system (CD4 < 300/dl) [18].
\n\t\t\tA seropositive gestating woman should be clinically addressed based on a multidisciplinary and thorough assessment of her initial health status. The latter should include a full physical examination, especially observing those signs that guide diagnosis towards an opportunistic infectious pathology and assessing the current immune status. Upon indicating the therapeutic and/or prophylactic antiretroviral treatment, a risk versus benefit assessment should be carried out to evaluate the effectiveness of the pharmacological scheme and the eventual teratogenic and toxic effects on mother and fetus.
\n\t\t\tThe following laboratory tests might be performed in addition to the routine tests that should be requested for pregnant women at the beginning of their prenatal follow-up [4,16]:
\n\t\t\tInfectious parameters:
\n\t\t\t- Rubella serology
- Urine culture
- Hepatitis B surface antigen Hepatitis B core antigen for Hepatitis B virus.
- Serology for the detection of Syphilis (RPR or VDRL).
- Serology for Hepatitis C.
- PPD (skin test for tuberculosis).
- Serology for certain parasitoses depending on their geographic prevalence (Toxoplasma gondii, Chagas disease, Malaria, etc.).
- Serology for cytomegalovirus.
- Culture for gonococcus, Chlamydia, Mycoplasma and Ureaplasma.
Immunological parameters:
\n\t\t\t- CD4+ T cell counts
- Viral load assessment (PCR).
Sequential detection of the viral load and CD4 counts are used to predict the risk of a rapid disease progression in the pregnant woman and the eventual VT in such patient group. However, as an intent to identify a more cost-effective test than the latter, the role of HIV typification through sequential study of specific bands offered by the Western blot technique has been studied recently. Such preliminary studies demonstrated that the absence of anti pol antibodies was associated with an acute infection. Although it is true that the lack of anti gag p39 antibodies was related to a rapid disease progression and a higher probability of infection of the newborn, such absence was not as statistically significant to predict a higher risk for VT. Therefore, such diagnostic tool needs still to be upheld by further studies before it becomes indicated for clinical use. [29]
\n\t\t\tAll antenatal diagnostic assessments may be carried out without contradictions, except for those involving invasive techniques that imply an additional infection risk to the fetus (chorionic villus biopsy, amniocentesis, cordocentesis).
\n\t\tThe aim of antiretroviral therapy during pregnancy is to decrease the maternal viral load to undetectable levels without causing deleterious or teratogenic effects on the product of conception, and on the other hand, to decrease the risk of vertical transmission. To attain such goal, there are currently 14 antiretroviral drugs available (Table 1). Such drugs must be used within schemes individually adapted for each patient. Drug selection should be based on the prior treatment of the woman (if she were under any), the current status of the patient and her motivation, the viral load, drug resistance, CD4+ T cell counts, and associated toxic and teratogenic effects (Table 2). The use of Zidovudine is recommended within the scheme. Zidovudine has been the only drug to enter a protocol and that has demonstrated efficacy in the protection of the fetus from vertical transmission. However, new studies have demonstrated the efficacy of other antiretroviral drugs in VT reduction.
\n\t\t\t\n\t\t\t\t\t\tGeneric name | \n\t\t\t\t\t\tFDA Classs | \n\t\t\t\t\t
Abacavir | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Didanosine (ddI) | \n\t\t\t\t\t\tB | \n\t\t\t\t\t
Lamivudine (3TC) | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Lamivudine + Zidovudine (Convivir) | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Stavudine (d4T Zalcitabine) | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Zidovudine (ZDZ, AZT) | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Non-nucleosidic reverse transcriptase Inhibitors | \n\t\t\t\t\t|
Delavirdine | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Efavirenz * | \n\t\t\t\t\t\tX | \n\t\t\t\t\t
Nevirapine | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Protease inhibitors | \n\t\t\t\t\t|
Amprenavir * | \n\t\t\t\t\t\tX | \n\t\t\t\t\t
Indinavir | \n\t\t\t\t\t\tC | \n\t\t\t\t\t
Nelfinavir | \n\t\t\t\t\t\tX | \n\t\t\t\t\t
Ritonavir | \n\t\t\t\t\t\tB | \n\t\t\t\t\t
Saquinavir | \n\t\t\t\t\t\tB | \n\t\t\t\t\t
ANTIRETROVIRAL AGENTS,Nucleosidic reverse transcriptase inhibitors
A: Controlled studies show no risk | \n\t\t\t\t\t
B: No evidence of risks in humans | \n\t\t\t\t\t
C: Risks cannot be ruled out. However, a potential benefit might justify its use. | \n\t\t\t\t\t
D: Positive evidence of risk. | \n\t\t\t\t\t
X: Contraindicated in pregnancy. | \n\t\t\t\t\t
FDA Drug Category Rankings (Drugs and pregnancy)
The first formalized intent in prevention of VT was that assessed by a joint study carried out in France and the United States, attempting at the evaluation of a management protocol (Clinical Group Protocol 076-ACTG 076) [11], consisting of a study and follow up of HIV+ pregnant women that had a gestational age between weeks 14 and 34, without antiretroviral therapy or indications for such therapy, with CD4+ T cell count > or equal to 200 cells/mm3. The group that was administered placebo was compared to the group receiving AZT (orally during pregnancy, injectable during delivery and as syrup to the newborn for 6 weeks). Results showed that transmission was 8.3% with AZT and 25% with placebo, which is equivalent to a reduction in 67% (p= 0,00006). (Table 3)\n\t\t\t
\n\t\t\tPrepartum: AZT between weeks 14 and 34: AZT 100 mg po 5 times per day or AZT 200 mg po 3 times per day or AZT 300 mg po 2 times per day | \n\t\t\t\t\t
Intrapartum: AZT 2 mg/kg intravenous during one hour,Followed by continuous infusion of 1 mg/kg until delivery | \n\t\t\t\t\t
Postpartum: AZT to the neonate from 8 to 12 hours after birth in 2 mg/kg doses (syrup) every 6 hours during the first 6 weeks of life | \n\t\t\t\t\t
ACTG 076 PROTOCOL
The first attempt at a successful pharmacological scheme to control VT was achieved by the ACTG 076 protocol. Such protocol together with elective C-section and suppression of lactation (biomedical measures) achieved a decrease in VT from 29% to 5.6% [11]. Although the latter is true, new evidence demonstrated that the triple drug therapy was more effective than monotherapy or bitherapy to prevent Vertical Transmission (VT). A protocol, that combined the biomedical preventive measures already mentioned and the indication of three antiretroviral drugs was designed. Such drugs included nucleosidic and non-nucleosidic reverse transcriptase inhibitors (NRTI and NNRTI respectively) and Protease inhibitors (PI), and together formed a series of schemes known as highly active antiretroviral therapy (HAART). It is by virtue of the latter that VT has decreased to values close to 1.0 [2-6, 30-34].
\n\t\t\tIt is a known fact that VT may occur among seropositive pregnant women during pregnancy (35%), delivery (65%) and lactation (14%-29%) and that there are factors that increase the risk of fetal infection (Primoinfection, Sexually transmitted diseases and CD4+ T cell counts). The most important of such factors is maternal viral load [27]. Loads under 1000 copies/ml have significantly lower risks of VT, however there is no evidence pointing to the minimal load that exempts from risk. The latter supports the need to use a highly active antiretroviral therapy (HAART) with the highest effectiveness and safety to reach, hopefully, undetectable viral load levels. With such purpose, and considering that most of transmissions to the newborn occur during the peripartum period, an attempt at reaching the lowest viral loads during the third trimester of gestation (weeks 34-36) should be made. However, due to the potential toxic effects of therapeutic drugs, it is suggested their use is limited to the periods of maximum effectiveness considering risks and benefits of such exposure to the mother-child binomial. Anyway, AZT should be added to the therapeutic scheme if possible, even in cases in which such drug was not used during the antepartum period, since it has proven to be helpful to decrease vertical transmission even in abbreviated schemes (intrapartum and postpartum) [4,5,34].
\n\t\t\tBased on the above-mentioned, HAART type ART should be indicated in the following situations: [34]
\n\t\t\tIn seropositive pregnant women without prior treatment from week 24
In pregnant women with viral loads higher than 100,000 copies/ml from 14 weeks
In case of seroconversion during pregnancy it should be indicated at once
Within the HAART concept, the selection of the NRTI combination to be used should follow the efficacy of the latter in reducing VT, considering the potential teratogenic effects and the eventual toxicity to the mother-child binomial. Based on the teratogenesis risk classification of the FDA, NRTI are classed as B or C. The largest experience involves Zidovudine (AZT or ZDV) that has demonstrated being quite a safe drug, with low resistance and high efficacy to prevent VT. In addition, the association of ZDV and Lamivudine (ZDV/3TC) has demonstrated to be more effective than ZDV as monotherapy in mother-to-child transmission prevention. Such combination does not imply higher toxicity or risk of teratogenesis [2-6, 30-34].
\n\t\t\tRegarding the search for the third drug, Lopinavir-Ritonavir has demonstrated efficacy and safety in VT prevention. The association of Saquinavir reinforced with Ritonavir has gathered enough evidence to suggest that such combination is a good supplementary alternative to render the pharmacological therapy more effective [26].
\n\t\t\tAlthough Nevirapine (NVP) has been widely indicated and has demonstrated being effective in the prevention of mother-to-child transmission mostly in developing countries with low economical resources, the use of such drug has been related to the development of viral resistance both in mothers as in children who were infected despite the received prophylaxis. Moreover, mothers who were administered Nevirapine had a higher incidence of toxic effects (hepatic, hypersensitivity) in particular pregnant women with CD4+ T cell counts higher than 250 cells/ml. The above mentioned suggests that such indication should be considered among patients never having received Nevirapine and with CD4+ T cell counts under 250 cells/ml. When such drug is used in the intrapartum period, it is advisable to indicate ZDV y Lamivudine (3TC) for 7 days both to the mother as well as to the newborn, to reduce the risk of viral resistance to Nevirapine and other NNTRI [30-34].
\n\t\t\tThe following are among the drugs that should not be indicated during pregnancy: Efavirenz, Nelfinavir and the association of d4T (Stavudine) and ddI (Didanosine). All share teratogenicity and toxicity risk for the mother-child binomial [30-36].
\n\t\t\tIn 2010 the World Health Organization stressed the importance of offering a lifelong antiretroviral therapy to patients with a carrier condition recognized during pregnancy. The WHO proposed two prophylactic treatment schemes (A and B) for pregnant women who did not meet the criterion of a certain CD4+ T cell count (<350/ mm3). A third option (B+) as appeared recently, aiming at implementing the HAART for a lifetime to all seropositive pregnant women regardless of their CD4+ T cell count (Table 4). This new option has the following advantages: it simplifies drug supply, since it relates drugs to national antiretroviral therapy programs, protects against VT, prevents transmission to seronegative partners and prevents discontinuation of the follow up of therapies already implemented by the patients. It finally suggests that such new option should be evaluated depending on the reality of each country [31].
\n\t\t\t\n\t\t\t\t\t\t | \n\t\t\t\t\t\t\tWoman Receives:\n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t | |
\n\t\t\t\t\t\t\tTreatment\n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tProphylaxis\n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tInfant receives:\n\t\t\t\t\t\t | \n\t\t\t\t\t|
(for CD4 count \n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t(for CD4 count > 350 cells/ mm3) | \n\t\t\t\t\t||
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tOption Aa\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\tTriple ARVs starting as soon as diagnosed, continued for life \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAntepartum: AZT starting as early as 14 weeks gestation \n\t\t\t\t\t\t\tIntrapartum: at onset of labour, single-dose NVP and first dose of AZT/3TC \n\t\t\t\t\t\t\tPostpartum: daily AZT/3TC through 7 days postpartum | \n\t\t\t\t\t\tDaily NVP from birth until 1 week after cessation of all breastfeeding; or, if not breastfeeding or if mother is on treatment, through age 4–6 weeks \n\t\t\t\t\t\t | \n\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tOption B\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\ta\n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSame initial ARVs for both\n\t\t\t\t\t\t\tb\n\t\t\t\t\t\t\t:\n\t\t\t\t\t\t\t \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t Triple ARVs starting as soon as diagnosed, continued for life \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSame initial ARVs for both\n\t\t\t\t\t\t\tb: \n\t\t\t\t\t\t\t Triple ARVs starting as early as 14 weeks gestation and continued intrapartum and through childbirth if not breastfeeding or until 1 week after cessation of all breastfeeding | \n\t\t\t\t\t\tDaily NVP or AZT from birth through age 4–6 weeks regardless of infant feeding method \n\t\t\t\t\t\t | \n\t\t\t\t\t
\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tOption B+ \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSame for treatment and prophylaxis\n\t\t\t\t\t\t\tb: Regardless of CD4 count, triple ARVs starting as soon as diagnosed,c continued for life \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSame for treatment and prophylaxis\n\t\t\t\t\t\t\tb: Regardless of CD4 count, triple ARVs starting as soon as diagnosed,c continued for life \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t | \n\t\t\t\t\t\tDaily NVP or AZT from birth through age 4–6 weeks regardless of infant feeding method \n\t\t\t\t\t\t | \n\t\t\t\t\t
Note: “Triple ARVs” refers to the use of one of the recommended 3-drug fully suppressive treatment options. For the drug abbreviations in the table: AZT (azidothymidine, zidovudine [ZDV]); NVP (nevirapine); 3TC (lamivudine).
a Recommended in WHO 2010 PMTCT guidelines
b True only for EFV-based first-line ART; NVP-based ART not recommended for prophylaxis (CD4 >350)
c Formal recommendations for Option B+ have not been made, but presumably ART would start at diagnosis.
Options for PMTCT programs
\n\t\t\t
The eventual toxic effect of such medications on the mother-child binomial is among the aspects that need to be assessed for the election of the pharmacological treatment. According to study reports, approximately 80% of gestating women under treatment developed some side effect such as anemia, nausea, vomiting, hepatic enzyme disorders or hyperglycemia [26,35-37]. Because of this, it is important to know which are the side and toxic effects of the drugs that are commonly used, in order to identify them and treat them accordingly.
\n\t\t\tIn non-pregnant women, the use of protease inhibitors has been related to the development of different degrees of carbohydrate Intolerance. This should be considered when they are used during pregnancy since they may trigger gestational diabetes [26,35-37].
\n\t\t\tReverse transcriptase nucleoside inhibitors are recognized for their induction of mitochondrial dysfunction due to their affinity for mitochondrial DNA-polymerase gamma. Such effect is more intense for Stavudine (d4T), ddI (Didanosine) and less intense for ZDV (Zidovudine), 3TC (Lamivudine), ABC (Abacavir) and TDF (Tenofir). Additionally, these drugs are also related to lactic acidosis in cases with concomitant hepatic steatosis. Such association would be higher with the use of d4T (Stavudine) with an estimated rate of 0,8% and 1,2% per year per treated patient. [26, 35-37]. Clinical manifestations of this condition are varied and include polyneuritis, myopathies, cardiopathies, hepatic steatosis and lactic acidosis. Not uncommonly patients develop a condition similar to the HELLP Syndrome that should be considered when addressing differential diagnoses. Finally, there are reports about uninfected children, born to seropositive mothers that received ZDV or ZDV/Lamivudine (ZDV/3TC) during pregnancy, who developed mitochondrial dysfunction –related symptoms during the first months of life. Such finding was not confirmed with the protocol assessment ACTG 076 [11].
\n\t\t\t\tRegarding the mode of delivery in seropositive pregnant women who did not receive ART or had partial indication of ART, elective C-section at week 38 (a surgical procedure carried out before the initiation of labor and without premature rupture of membranes) has demonstrated a decrease of VT risk in one half. [8,38]. Recent studies propose the option of vaginal delivery to be used according to the obstetric conditions in seropositive women with viral load under 1000 copies/ml and prior patient consent. Such indication is supported by the fact that C-section benefits are indeed difficult to evaluate and moreover, data retrieved from a large number of patients did not evidence a higher reduction of VT among patients with viral loads < 1000 copies/ml that underwent C-section. Furthermore, C-section increased infectious morbidity between 7 and 10 fold [33].
\n\t\t\t\tWhen facing the vaginal delivery option, episiorrhaphy and forceps or spatulas should be avoided. Invasive procedures such as amniocentesis, chorionic villus biopsy and invasive monitoring might increase fetal exposure to infected maternal blood, and thus should also be avoided. The use of oxytocin has no contraindications, as opposed to ergot-derivatives that might present an eventual synergic action in association to Protease Inhibitors that would exaggerate vasoconstriction and ischemia, and therefore are contraindicated [39].
\n\t\t\t\tDuring delivery (C-section or vaginal delivery), the indication of intravenous administration of ZDV to the mother should be the rule, since fetal plasma levels of such drug, reached by transplacental route, ensure an adequate pre-exposition prophylaxis. Such indication together with the administration of ZDV suspension orally to the newborn during six weeks increases the preventive effect on infection transmission. This is regardless of the mother being administered ZDV within the therapeutic scheme or even in the event of resistance to ZDV. Finally, the use of Nevirapine (200 mg one time only dose) should only be indicated to patients with late initiation of the prevention protocol, on patients with a viral load > 1000 copies/ml or in the case of diagnosis of maternal carrier status during labor [4,5,33,34].
\n\t\t\t\tThere is evidence pointing that among patients that are not treated within an antiretroviral management protocol, transmission to the newborn through breastfeeding ranges between 5% and 14% [9,40]. Free and cell-bound virus has been isolated from breast milk through PCR techniques and viral culture. Such cells are more numerous in the colostrum and in breast milk secreted during the immediate puerperium. The latter, in association with the immature immune system of the newborn, make transmission through breastfeeding higher during the first month of life. All the above-mentioned, warrant the recommendation to suppress lactation in countries where infantile malnutrition and diarrheic syndrome - related mortality are low [34].
\n\t\t\tEvery pregnant woman should be offered the possibility of undergoing HIV testing not later than upon the second pregnancy follow-up visit within the first trimester of gestation, and depending on resources, also within the third trimester.
A quick HIV test for HIV diagnosis enabling immediate action to be taken should be offered to women who arrive to delivery without having their test results available, even if tests have been carried out. Counseling and consent are mandatory.
ART is recommended to prevent HIV vertical transmission in pregnant women without prior therapy between gestation weeks 20 and 28. The use of ZDV in association with Lamivudine is recommended.
Viral loads should be followed up 6 weeks after initiation of ART during gestation and subsequently on a monthly basis until gestation weeks 34 and 36.
Elective C-section should be indicated at 39 weeks in HIV+ women without ART over pregnancy, in women that do not have a viral load result upon weeks 34-36, in those with a viral load > 1.000 copies/ ml or in women co-infected with Hepatitis C virus.
In the event a pregnant woman meets the conditions for a vaginal delivery, her consent should be obtained after being informed about the eventual associated risks. Episiorrhaphy and all procedures involving the use of instruments should be avoided (forceps or spatulas).
Intrapartum intravenous ZDV should be used regardless of the delivery mode chosen.
ZDV suspension should be administered orally for 6 weeks starting from 8 to 12 hours from birth, to all newborns to HIV+ mothers. The recommended ZDV dose for term newborns is 2 mg/Kg/dose every 6 hours p.o. or 1.5 mg/Kg/dose every 6 hours intravenous. The same dose should be administered every 12 hours in preterm newborns of less than 35 weeks gestational age.
If Nevirapine is administered intrapartum, ZDV/3TC must be associated for 7 days after delivery to reduce the risk of developing NVP resistance.
Lactation should be suppressed with cabergoline or bromocriptin.
The newborn should be administered ZDV suspension, orally, for 6 weeks starting from 8 to 12 hours after birth. The recommended AZT dose for term newborns is 2 mg/ Kg/dose every 6 hours orally or 1.5 mg/Kg/dose every 6 hours intravenous. The same dose should be administered every 12 hours in preterm newborns of less than 35 weeks gestation.
Newborns to mothers who received NVP as part of mother-to-child transmission prevention should receive, besides ZDV, 2 doses of 2 mg/Kg of NVP oral solution. The first dose should be administered the earliest as possible postpartum and the second should be administered at 48 to 72 hours of life.
The newborns to mothers who did not receive the mother-to-child transmission prevention protocol, or who just received intrapartum prophylaxis, should be administered the AZT scheme and 1 to 2 NVP doses.
A seropositive gestating woman should be clinically addressed based on a multidisciplinary and thorough assessment of her initial health status. The latter should include a full physical examination, especially observing those signs that guide diagnosis towards an opportunistic infectious pathology and assessing the current immune status.Once the effectiveness of biomedical healthcare provisions for the prevention of MTCT (mother-to-child-transmission) is demonstrated, it is important to ensure collection of epidemiological history in order to achieve an adequate report, key data to reassess the design and the effectiveness of preventive programs. To achieve such aims, it is critical to maintain and improve diagnosis and primary prevention of the infection among women in childbearing age. ON the other hand, it is important to prevent high rates of unwanted pregnancies and abortions that are direct indicators of risk behaviors in such population group. Likewise, one should aim at achieving 100% screening during the first trimester, also at the possibility of repeating it during the third trimester and at training maternity staff on rapid testing for carrier status detection during labor, for those pregnant women without having accessed an AMTCPP (Antenatal Mother-to-Child Prevention Program).
\n\t\t\tFinally, MTCT prevention strategy has been based on the ongoing revision of the pooled evidence, therefore it is of key importance to continue evaluating new conducts that enable identification of other aspects: the eventual induction of antiviral resistance and toxicity on the pregnant woman and the newborn and their potential impacts on further quality of life, the use of micronutrients and their impact on MTCT decrease, assessment of the vaginal delivery option in gestating women with low viral load, and sperm wash as an element to reduce MTCT [40].
\n\t\t\n\t\t\t\tVT: Vertical Transmission:
\n\t\t\t\n\t\t\t\tHIV: Human Immunodeficiency Human
\n\t\t\t\n\t\t\t\tAIDS: Acquired Immune Deficiency Syndrome
\n\t\t\t\n\t\t\t\tPMTCT: Prevention of mother-to-child transmission
\n\t\t\t\n\t\t\t\tAMTCPP: Antenatal Mother-to-Child Prevention Program
\n\t\t\t\n\t\t\t\tUNAIDS: Joint United Nations Program on HIV/AIDS
\n\t\t\t\n\t\t\t\tART: Antiretroviral Therapy
\n\t\t\t\n\t\t\t\tHAART: Highly Active Antiretroviral Treatment
\n\t\t\t\n\t\t\t\tNRTI: Nucleoside reverse transcriptase inhibitor
\n\t\t\t\n\t\t\t\tNNRTI: Non nucleoside reverse transcriptase inhibitor
\n\t\t\t\n\t\t\t\tPI: Protease inhibitor
\n\t\t\t\n\t\t\t\tAZT or ZDV: zidovudine
\n\t\t\t\n\t\t\t\tNVP: Nevirapine
\n\t\t\t\n\t\t\t\t3TC: Lamivudine
\n\t\t\td4T: Stavudine
\n\t\t\tddI: Didanosine
\n\t\t\t\n\t\t
Cardiomyopathies are categorized based on their phenotype. In that context, dilated cardiomyopathy (DCM) is characterized by a dilated left ventricle (LV), typically with thin walls, and systolic dysfunction (\nFigure 1\n). Sometimes the dysfunction is not limited to the left ventricle but also affects the right ventricle. It is estimated that approximately 1 in 2500 people suffer from DCM [1]. The causative pathways are often complex, and several risk factors work together. In the vast majority of patients, there is a history of hypertension. Other well-known etiologies are myocarditis, chemotherapy, toxins, radiation, and coronary artery disease. However, when a causative reason for the dilation of the heart cannot be identified, DCM is considered idiopathic. About 20–50% of idiopathic DCM is considered to be of a genetic origin, being consequently hereditary [2]. Interestingly, only in 30–40% of cases of familial DCM can a specific gene be identified [3].
\nNormal and dilated left ventricle in parasternal short-axis view.
In hereditary DCM, there is variability among phenotypes, and the manifestation of LV dysfunction is heterogeneous. More than 50 genes are associated with the disease [4] (\nTable 1\n). Many of the gene mutations responsible for DCM affect the cell structure called sarcomere, which is involved in cardiac contractility. That is why some of those genes may be responsible for the development of hypertrophic cardiomyopathy as well. In 20% of the cases of hereditary DCM, mutations of the titin (TTN) gene are found, which encodes the protein titin found in the sarcomere [5].
\nGene | \nCellular structure | \n
---|---|
ABCC9 | \nCalcium/sodium handling | \n
ACTC1 | \nSarcomere and cytoskeleton | \n
ACTN2 | \nSarcomere and cytoskeleton | \n
ANKRD1 | \nSarcomere and transcription factor | \n
BAG3 | \nSarcomere | \n
CRYAB | \nCytoskeleton | \n
CSRP3 | \nSarcomere and cytoskeleton | \n
DES | \nCytoskeleton | \n
DMD | \nCytoskeleton | \n
DSG2 | \nDesmosome | \n
EYA4 | \nOther | \n
FLNC | \nCytoskeleton | \n
GATAD1 | \nOther | \n
LAMA4 | \nExtracellular matrix proteins | \n
LCB3 | \nCytoskeleton | \n
LMNA | \nNuclear envelope | \n
MYBPC3 | \nSarcomere | \n
MYH6 | \nSarcomere | \n
MYH7 | \nSarcomere | \n
MYPN | \nCytoskeleton | \n
PLN | \nCalcium/sodium handling | \n
PSEN1 | \nOther | \n
PSEN2 | \nOther | \n
RBM20 | \nOther | \n
SCN5A | \nCalcium/sodium handling | \n
SGCD | \nCytoskeleton | \n
TAZ | \nOther | \n
TCAP | \nSarcomere and cytoskeleton | \n
TMPO | \nNuclear envelope | \n
TNNC1 | \nSarcomere | \n
TNNI3 | \nSarcomere | \n
TNNT2 | \nSarcomere | \n
TPM1 | \nSarcomere | \n
TTN | \nSarcomere | \n
VCL | \nSarcomere and cytoskeleton | \n
The main genes associated with hereditary dilated cardiomyopathy and the cellular structure that they regulate.
The inheritance pattern is autosomal dominant in the vast majority of the cases, which means that an individual has a 50% chance to inherit the gene if one of the parents carries it. In other cases, the pattern is autosomal recessive, which means that if both parents are affected, there is a 25% chance of inheriting the disease genotype. X-linked patterns, in which the gene is inherited through an X chromosome, have also been reported. In some cases, it is possible that the carrier may not develop the phenotype of the disease due to variable penetrance of the disease.
\nInherited DCM is defined by (a) the presence of two or more affected individuals in a single family who fulfill DCM criteria; fractional shortening <25% and/or ejection fraction <45% and left ventricular end diastolic diameter > 117% of the upper reference level corrected for age and body surface area based on Henry’s formula or (b) the presence of a first-degree relative with unexplained sudden death before the age of 35 years [6].
\nSymptoms of DCM are due to ventricular dysfunction and compensatory left ventricular remodeling as well as the involvement of the electrical conduction system of the heart [7]. Symptoms vary among patients, even if they are members of the same family [5]. Symptoms can occur at any age; typically, they first appear in mid-adulthood. Patients often report breathlessness, swelling of the legs, fatigue, chest pain, and arrhythmias, ranging from palpitations and syncope to fatal arrhythmias that cause SCD. Unfortunately, SCD is sometimes the first manifestation of the disease.
\nSudden cardiac death (SCD) is defined as the sudden and unexpected death of a person who was otherwise stable prior to the event [8]. If the death is witnessed and occurs within 1 hour of onset of symptoms, it is classified as SCD. If the sudden and unexpected death is not witnessed, then SCD is declared if it occurs within 24 hours of the person last being seen alive and well.
\nIn the case of hereditary cardiomyopathies, such as DCM, SCD occurs due to the development of fatal ventricular arrhythmias: ventricular tachycardia (VT) and ventricular fibrillation (VF) are most common, but prolonged bradycardia does occur. Possible underlying mechanisms for the initiation of a fatal re-entry arrhythmia in a DCM patient may include: (a) conduction block caused by a reduction of myocytes and hypertrophy and (b) continuous re-entry regeneration due to increased fibrosis, interstitial, and perivascular as well as post-necrosis fibrosis [9, 10]. Non re-entry mechanisms, such as focal automaticity, electrolyte disturbances, and stretch-induced arrhythmias, also contribute to the presentation of arrhythmias [10]. In particular, focal automaticity predisposes a patient to nonsustained VT (NSVT) [11].
\nDCM ranks third as the cause of SCD among cardiomyopathies, after arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy. SCD accounts for roughly a third of all-cause mortality among hereditary DCM patients. Rates of SCD vary among the patients in regard to their New York Heart Association (NYHA) functional status (\nTable 2\n). Notably, in patients with NYHA class I and II, 50–60% of deaths are classified as sudden, while in NYHA class IV patients, only 20–30% of deaths are sudden [10]. This is explained by the fact that in NYHA class IV, most patients die from progressive heart failure [12]. In most cases, potentially fatal arrhythmias present in a setting of systolic ventricular dysfunction, although the proportion of SCD is higher among patients with lower NYHA status. However, there is a subset of patients (reported to vary from 2% to one third of the DCM population) who present early in the disease course with life-threatening arrhythmias (Table 3) or unexplained syncope that are not related to the severity of LV dysfunction [13, 14]. This specific entity is referred to as arrhythmogenic DCM (AR-DCM). Patients who suffer from AR-DCM, compared to other DCM patients, have a higher risk of experiencing major arrhythmic events and SCD. Thus, a family history of SCD in an AR-DCM patient results in a higher burden of life-threatening arrhythmias and a higher risk of SCD [7]. It is important to mention that DCM patients, due to their high incidence of atrial fibrillation, also have a higher risk for ischemic stroke. However, it should be noted that if a cause of death other than arrhythmia is confirmed, the death will not be classified as sudden.
\nNYHA | \nRisk of SCD | \n
---|---|
Class I | \n50–60% | \n
Class II | \n50–60% | \n
Class III | \n20–30% | \n
Class IV | \n20–30% | \n
Risk of sudden cardiac death as a proportion of overall mortality according to New York Heart Association classification.
Factors associated with a high risk of arrhythmias | \n|
---|---|
Clinical | \nLow LVEF (<25–30%) Absence of beta-blockers AR-DCM Family history of SCD | \n
Ambulatory | \nQRS duration QT dynamicity T-wave alternans NSVT on Holter monitoring | \n
Imaging | \nMidwall late gadolinium enhancement Impaired global longitudinal strain Mechanical dispersion | \n
Genetic | \nDesmosomal mutations LMNA mutation SCN5A mutation FLNC mutation RBM20 mutation PLN mutation | \n
Factors associated with a high risk of life-threatening arrhythmias.
It is crucial to identify patients at high risk of a fatal arrhythmia. There are clues in the clinical history, electrocardiographic, imaging characteristics, and specific genetic features that need to be taken into account. Factors such as QRS duration, QT-interval dispersion, and T-wave alternans have been suggested as risk markers [15]. A considerable burden of ventricular arrhythmias (runs of VT) is usually present in a setting of advanced ventricular dysfunction with left ventricular ejection fraction (LVEF) <25%, which is a validated risk factor. Survived cardiac arrest and sustained ventricular tachycardia with hemodynamic compromise imply a high risk of recurrent arrhythmia and are classified as secondary prevention for an implantable cardioverter defibrillator (ICD) [16]. Unexplained syncope may be secondary to arrhythmia and constitutes a risk factor [15]. In the Marburg Cardiomyopathy study (MACAS), which excluded patients with a history of sustained VT or VF, unexplained syncope within the previous 12 months, and amiodarone therapy, it was shown that a low LVEF (<30%) was the only independent factor for major arrhythmic events. Patients with NSVT and patients who were not on beta-blockers upon enrollment also run a high risk for ventricular arrhythmias. Thus, the combination of documented NSVT on Holter monitoring with a low LVEF (<30%) increased the arrhythmic risk by eight-fold [17]. Family history of SCD, defined as SCD in a first degree relative <40 years of age or SCD in a relative with confirmed DCM at any age, is also an established risk factor.
\nImaging can be used to predict arrhythmia risk. In cardiac magnetic resonance imaging, midwall late gadolinium enhancement (LGE) can detect fibrosis. Even if magnetic resonance imaging is not able to detect fibrosis, it may still be found by advanced T1 mapping techniques before and after gadolinium infusion. This is a prominent finding due to the fact that it corresponds to macroscopic midmyocardial fibrosis on postmortem examination [18]. In echocardiography, an impaired global longitudinal strain, a marker of myocardial regional contractility, may reflect myocardial fibrosis [19]. It has been demonstrated that an impaired global longitudinal strain is associated with increased arrhythmic events [20]. A predictor of arrhythmias is also mechanical dispersion, which is defined as the standard deviation of the time to peak negative strain among the different myocardial segments [20].
\nRegarding genetic factors, DCM patients who carry a desmosomal or LMNA (lamin A/C) mutation run a higher risk of life-threatening ventricular arrhythmias and SCD, regardless of their LVEF. Patients who carry the LMNA gene, which encodes the type V intermediate filament protein, tend to have more life-threatening arrhythmias compared to other variant carriers and variant-negative patients [21, 22]. LMNA mutations are associated with high morbidity and mortality and with a high clinical penetrance [23]. For the LMNA carriers, various risk factors have been identified. These include NSVT during electrocardiogram monitoring, truncating mutations, LVEF <45–50%, and male sex [24, 25]. More recently, 1st degree AV block has been identified as another risk factor in LMNA carriers [26]. Desmosomal gene mutations are present in around 3% of DCM patients. They are also frequent in ARVC patients, creating a genotype overlap between the two cardiomyopathies. They have been associated with a high risk of potentially fatal arrhythmias, independently from the LVEF [21]. The SCN5A (sodium voltage-gated channel alpha subunit 5) gene, which provides instructions for making sodium channels, is also associated with conduction defects and ventricular arrhythmias [10]. Also associated with a higher risk of arrhythmic events are mutations in the FLNC gene, which encodes filamin proteins; the RNA-binding motif protein 20 gene (RBM20 gene), which encodes a protein that regulates splicing and the phospholamban (PLN) gene, which encodes a protein that inhibits a sarcoplasmic ATPase [21, 27]. In a 2019 study, it was demonstrated that RBM20 mutation carriers were more likely to have NSVT and sustained VT than idiopathic DCM cohorts [28]. The AR-DCM phenotype is associated with a high risk of fatal arrhythmias. Spezzacatene et al. identified the AR-DCM phenotype as well as a family history of SCD or sustained VT/VF as the only early significant predictors for SCD or sustained VT/VF in the overall DCM population. Interestingly, the AR-DCM phenotype is associated with a higher risk of arrhythmias, irrespective of LV dilatation and dysfunction, which is in contradiction to the general DCM population, where a low LVEF is associated with a higher arrhythmic risk [14]. However, AR-DCM is not associated with a poorer prognosis due to non-arrhythmic events, including heart failure [14].
\nMost DCM patients present with heart failure and are at a high risk of death. The primary management of such patients lies in the stabilization of progressive heart failure. Drugs like renin-angiotensin-aldosterone system (RAAS) antagonists and beta-blockers are first-line management in patients with DCM and reduce the risk of SCD by preventing ventricular remodeling. Angiotensin converting enzyme inhibitors (ACEs)/angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers are recommended, unless contraindicated or not tolerated. Furthermore, the combination of sacubitril/valsartan has been shown to be superior to ACE inhibitors and tends to replace them in the treatment of patients who are still symptomatic patients despite optimal medical treatment [16]. The anti-diabetic drug, dapagliflozin, seems to reduce the risk of worsening heart failure and death in patients with a reduced LVEF as well, regardless of the presence of diabetes mellitus, as proven in Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) study [29]. In NYHA IV patients, asystolic arrest and pulseless electrical activity are a frequent cause of death [10]. Cardiac resynchronization therapy (CRT) and CRT with defibrillator (CRT-D) treatment also has a place in both symptomatic treatment and preventive management of such patients.
\nArrhythmia management in hereditary DCM patients follows the general recommendations as SCD prevention in patients with reduced LVEF (<35%) [7]. Thus, patients with diagnosed DCM must be carefully evaluated for ventricular arrhythmias. Regarding drug management, amiodarone has not been proven to further reduce overall mortality or arrhythmic risk in the Amiodarone versus Implantable Defibrillator (AMIOVIRT) study, which showed that DCM patients who were on amiodarone did not have a statistically significant difference in terms of survival, compared to patients who received an ICD [30]. However, in the Sudden Cardiac Death in Heart Failure trial (SCD-HeFT) which enrolled patients with an LVEF <35% and NYHA II or III despite optimal medical therapy and compared ICD insertion vs. amiodarone vs. placebo, ICD therapy conferred a significant benefit in patients in NYHA class II, but not in class III. Furthermore, amiodarone, when compared to placebo therapy, showed no benefit in NYHA Class II patients and decreased survival among NYHA Class III patients. Results varied among NYHA classes but did not vary between heart failure of ischemic or nonischemic origin [31]. The Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure (DANISH) trial concluded that prophylactic ICD implantation in symptomatic patients with nonischemic heart failure did not offer a significantly lower long-term rate of death from any cause when compared to standard clinical care but decreased the incidence of SCD by 50% [32].
\nICD implantation remains the main therapy in preventive management for DCM patients with impaired LV function, who run a high risk of fatal arrhythmias. Guidelines, as well as the Expert Consensus Statement, recommend an ICD implantation in DCM patients with an LMNA gene mutation and risk factors such as NSVT observed during monitoring, male sex, truncating mutations (class IIa, level B), and an LVEF <45%, which is a higher cutoff value than used in heart failure population guidelines [22, 33].
\nIn addition, a primary-prevention ICD should be considered in DCM patients with both an arrhythmogenic phenotype and a family history of SCD or ventricular arrhythmias, irrespective of their LVEF or LV end-diastolic diameter, as they compose a high-risk group for major arrhythmic events and SCD [14]. However, in individual cases, it can be challenging to determine in which particular patients the benefits of ICD implantation would outweigh the risks. The DEFINITE study (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) randomized 458 patients with nonischemic DCM (LVEF <36%) and premature ventricular complexes or nonsustained VT, between standard medical therapy and ICD implantation. SCD by arrhythmias during a mean follow-up of 29 months was far fewer in the ICD group, proving the efficacy of defibrillation [34]. Yet, the use of LVEF alone is not always helpful in determining which patients would most benefit from an ICD. This was made clear in the Oregon and Maastricht Registries, in which 80% of SCD victims had an LVEF >35% [35, 36].
\nCRT is recommended in patients with sinus rhythm, NYHA class III/IV heart failure, LVEF ≤35%, and QRS >120 ms and/or evidence of mechanical dyssynchrony. It has been shown to offer great survival benefits as well as improvement of LV function in DCM patients [37]. This has been observed especially in women, who seem to benefit more than men from CRT [38]. Furthermore, it has been proven that in patients with nonischemic DCM with an LVEF ≤30%, NYHA class II, and QRS duration ≥130 ms, CRT-D device implantation was also beneficial in reducing the risk of death or heart failure when compared with defibrillation only [39]. On the other hand, patients with low LVEF heart failure and permanent atrial fibrillation do not seem to derive extra benefit from a CRT-D device compared with standard ICD treatment, as suggested by the Resynchronization for Ambulatory Heart Failure Trial (RAFT) trial [40]. Of interest in DCM patients, LGE was proven to be a strong, independent predictor of arrhythmic events and was suggested to improve risk stratification for SCD and better identify the need for ICD therapy [41].
\nDecisions about ICD therapy should incorporate genetic factors. In patients with mutations, i.e. LMNA mutations, the conventional LVEF-threshold based guidelines for ICD do not apply. In fact, an ICD may be considered for a patient with higher LVEF thresholds [26, 42]. Regarding FLNC mutations, 20% of patients with a primary-prevention ICD who carry the mutation had an appropriate ICD shock, much higher than in unselected DCM populations [43]. Appropriate ICD shocks are also more likely in PLN carriers, especially in R14del variant, along with a family history of SCD before the age of 50 years compared to those who do not carry the mutation [44]. These findings support the hypothesis that genetic factors should be considered early in the disease progression.
\nThe CMR-Guide (Cardiac Magnetic Resonance Guided Management of Mild-Moderate Left Ventricular Systolic Dysfunction) trial, which is expected to be completed in 2020, is randomizing ischemic and nonischemic cardiomyopathy patients with an LVEF between 36 and 50% and presence of LGE to either an ICD or an implantable loop recorder in an attempt to determine whether LGE is a sufficient marker alone or whether genetic characterization is also necessary in risk stratification. In general, a polyparametric integration is being introduced in the primary prevention of SCD through ICD implantation in DCM patients that includes family history of SCD, LVEF, late gadolinium enhancement, and possibly genetic parameters [45].
\nThe evaluation and treatment of hereditary DCM constitutes an emerging field. Still, risk stratification regarding SCD is based on general knowledge. Larger registries and long-term follow-up may elucidate more specific risk markers associated with genotypes in addition to phenotype.
\nHereditary DCM is a heterogeneous condition, which may lead to advanced HF as well as SCD. Risk stratification and preventive management strategies are challenging. Many factors must be considered in the management of patients with hereditary DCM. Gene mutations are surfacing and have already been proven to play a very significant role in clinical decisions. Moreover, based on new data and studies, the profile of each DCM patient tends to be better understood. As a result, both therapy and prevention evolve and ameliorate in a way that will become individualized. ICDs are lifesaving but their role in different genotypic settings remains to be elucidated.
\nPeter Magnusson has received speaker fees or grants from Abbott, Alnylam, Bayer, AstraZeneca, Boehringer-Ingelheim, Lilly, MSD, Novo Nordisk, Octopus Medical, Pfizer, and Zoll. Joseph Pergolizzi is a principal at Native Cardio, Inc. Marianna Leopoulou and Jo Ann LeQuang have no relevant disclosures.
ACE | angiotensin converting enzyme |
ARB | angiotensin receptor blocker |
AR-DCM | arrhythmogenic dilated cardiomyopathy |
ARVC | arrhythmogenic right ventricular cardiomyopathy |
CMR | cardiac magnetic resonance |
CRT | cardiac resynchronization therapy |
CRT-D | cardiac resynchronization therapy defibrillator |
DCM | dilated cardiomyopathy |
ICD | implantable cardioverter defibrillator |
LGE | late gadolinium enhancement |
LMNA | lamin A/C |
LV | left ventricle |
LVEF | left ventricular ejection fraction |
NSVT | nonsustained ventricular tachycardia |
NYHA | New York Heart Association |
RAAS | renin-angiotensin-aldosterone system |
PLN | phospholamban |
RBM20 | RNA binding motif protein 20 |
SCD | sudden cardiac death |
SCN5A | sodium voltage-gated channel alpha subunit 5 |
TTN | titin |
VF | ventricular fibrillation |
VT | ventricular tachycardia |
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