Human imunodeficiency virus infection in pregnancy

HIV infection represents one of the major global public health challenges, especially among women of reproductive age. In 2020, there were 1.3 million pregnant women infected with HIV worldwide. Untreated HIV infection in pregnancy carries an increased risk of maternal and perinatal morbidity and mortality. Perinatal transmission of HIV refers to the transmission of the virus from mother to child during pregnancy, childbirth, or puerperium. The aim of this paper is to present the up-to-date information on diagnosis, treatment, and monitoring of pregnancy in HIV-positive women, with reference to the time and mode of delivery, in order to prevent the transmission of the virus from mother to fetus.

The main goals of monitoring and treating HIV infection during pregnancy are the following: preventing the transmission of the virus to the fetus, preserving the mother’s health, and providing conditions for a safe delivery. The goal of treatment is to maintain the lowest level of the virus in the blood, especially at the time of delivery, in order to reduce the risk of vertical transmission.

It is recommended to start treatment of HIV infection before pregnancy. Also, regular monitoring of the viral load, the CD4+ lymphocyte count, and blood count, as well as performing liver and kidney function tests, is necessary.

The choice of the time and mode of delivery should not differ in pregnant women with a low viral load, as compared to healthy pregnant women, while in pregnant women with a high viral load, the pregnancy should be ended with elective caesarean section.

HIV infection affects both the pregnant woman and the fetus. Therefore, antenatal, intrapartum, and postpartum monitoring is important. The decision on therapy, as well as the time and mode of delivery, should be individual, and made in accordance with the viral load, the clinical presentation of HIV infection of the mother, and the condition of the fetus.

INTRODUCTION

The first patients with acquired immune deficiency syndrome (AIDS) were described in 1981, and two years later, the cause of the disease was identified - human immunodeficiency virus (HIV) [1]. At the end of 2020, around 37.7 million people were infected with HIV worldwide, of whom 36 million were adults, and 1.7 million were children under the age of 14. Females made up 53% of the infected population. In 2020, 1.5 million new cases and 680,000 deaths were registered [2]. With this in mind, it is clear that HIV infection represents one of the greatest global public health challenges, especially among women of reproductive age.

Perinatal transmission of HIV refers to the transmission of the virus from mother to child during pregnancy, childbirth or breastfeeding. Untreated HIV infection in pregnancy is associated with adverse pregnancy outcomes, such as preterm birth, low birth weight, and stillbirth [3].

In 2020, there were 1.3 million pregnant women with HIV worldwide. A total of 85% of pregnant women used antiretroviral therapy to prevent virus transmission to the fetus [4]. It is owing to the administration of therapy that the transmission of HIV from mother to child was present in less than 1% of newborns, in 2018 [5]. In addition to affecting the fetus, HIV also has a significant impact on the health and quality of life of pregnant women. Frequent depressive episodes and suicidal ideas have been described in HIV-infected pregnant women, especially in those whose infection was diagnosed after conception. About 60% of pregnant women diagnosed with HIV during pregnancy showed signs of somatic disease [6].

The Atlanta Center for Disease Control highlights social and economic factors as the most important for safe pregnancy planning and monitoring the pregnancy of women with HIV [5].

EPIDEMIOLOGY AND ETIOLOGY OF HIV INFECTION

The global prevalence of HIV in the adult population, in 2020, was 0.7% [2]. The largest number of people with HIV infection live in Africa (over 25.3 million), followed by Asia (5.8 million), Western and Central Europe (2.2 million) and Latin America (2.1 million) [2].

A quarter of the infected persons in sub-Saharan Africa are in the female population aged 15 – 25 years. Approximately one-third (35%) of women in the world are exposed to physical/sexual violence, which in some regions increases the likelihood of HIV transmission. The most common route of transmission of the virus is by blood, and intravenous drug users are usually infected that way. Sexual transmission predominates in transgender persons, female sex workers, and younger homosexuals [2]. Transmission of the virus from mother to child, the so-called vertical transmission, is also possible. Without antiretroviral therapy, transmission of HIV from mother to child during pregnancy, childbirth, or breastfeeding occurs in about 15 – 45% of cases [4].

The virus was detected in almost all bodily secretions and excretions (blood, saliva, tears, cerebrospinal fluid, ejaculate). It enters the host organism through mucous membranes. HIV is not transmitted through air, water, mosquitoes or other insects, saliva or tears that are not mixed with the serum of an infected person, or social contacts (handshakes, hugs, kisses, sharing dishes, etc.) [4].

Owing to its lipoprotein envelope, HIV is extremely sensitive to fat solvents, detergents, acids and bases, as well as exposure to temperatures of above 60^o C lasting more than 30 minutes. It is resistant to the usual doses of radiation (ultraviolet, X-ray, gamma), so in order to inactivate the virus in this way, higher doses must be used with a shorter distance from the radiation source [7]. The virus can survive in blood in syringes, at room temperature, for up to 42 days, and in post-mortem blood and cerebrospinal fluid for up to 11 days [8],[9]. However, the virus has not been detected in amniotic fluid of pregnant women who were on antiretroviral therapy [10].

A virus similar to HIV, belonging to the same family and subfamily, was discovered in macaque monkeys. Therefore, it is believed that HIV originated from primates, from which it passed on to humans at the beginning of the 20th century [11]. According to its morphology, physical, chemical and biological properties, HIV belongs to the family Retroviridae, subfamily Lentivirinae (slow viruses). Based on the genetic differences of the viruses, there are three main groups (M, N and O). Over 90% of HIV infections originate from group M, which consists of nine subtypes of the virus. Subtype B is most often present in the countries of Western Europe and America [12]. HIV has two serological types: 1 and 2. HIV 1 is more frequently transmissible, is more aggressive in the early stages of the disease, and is more often transmitted from mother to child [13].

PATHOGENESIS OF HIV INFECTION

The pathogenesis of HIV infection is determined by the phenotype of the virus, as well as by the receptors/ coreceptors that allow the virus to enter host cells. HIV primarily infects CD4+ T lymphocytes, to which the viral envelope proteins gp 120 and gp 41 bind. Other cells susceptible to HIV infection are hematopoietic (macrophages, monocytes, dendritic cells, fetal thymocytes and thymic epithelial cells, B lymphocytes, megakaryocytes, natural killer cells, stem cells), cells of the central nervous system (microglial cells, astrocytes, oligodendrocytes, endothelial capillary cells), colonic epithelial cells, liver Kupffer cells, syncytial cells and trophoblastic placental cells [14]. For the entry of the virus into the cell, co-receptors that depend on the type of cells are necessary. The two main chemokine coreceptors are CCR5 and CKSCR4. Blood and tissue macrophages, dendritic cells, and T lymphocytes have these receptors [15]. The largest reservoirs of HIV are tissue macrophages. They can be found in the brain, lungs, lymph glands, skin, and bone marrow of infected individuals. Monocytes and macrophages are the main mediators in the spread of viruses through tissues. After the virus enters the host’s organism, rapid replication of the virus occurs, which affects the activation of CD8+ T lymphocytes that destroy HIV-infected cells. A good CD8+ T lymphocyte response is associated with slower disease progression [16]. In the chronic phase of the disease, there is continuous replication of the virus and consequent generalized immune activation in which proinflammatory cytokines also play an important role [17]. Macrophage-derived cytokines contribute to disease progression [18].

Humoral response to HIV infection is achieved primarily by neutralizing antibodies, which bind the virus and prevent it from infecting target cells. Neutralizing antibodies bind to infected cells and trigger effector cells, which induce cytolysis or apoptosis of infected cells [19].

The CCR3 co-receptor is believed to play a role in viral entry into fetal cells [20]. The placenta plays a key role in the transmission of HIV from mother to fetus. The virus can infect placental endothelial cells, Hofbauer macrophage cells, trophoblasts, and terminal chorionic villus cells. Placental cells produce various soluble factors that influence further HIV replication [21].

CLINICAL PRESENTATION OF HIV INFECTION

The clinical presentation of HIV infection can vary, from asymptomatic to the presence of severe opportunistic infections. Opportunistic infections are infections that occur in immunodeficient persons, such as persons infected with HIV, and they manifest more often or are more severe than usual infections. The World Health Organization categorized the clinical presentation of HIV infection into four stages. The first stage consists of asymptomatic infection or generalized lymphadenopathy lasting longer than six months. In the second stage, mild symptoms, such as weight loss of less than 10%, recurrent respiratory infections, and a number of skin diseases are present. The third stage is characterized by moderate symptoms such as greater weight loss, prolonged unexplained diarrhea, pulmonary tuberculosis, severe systemic bacterial infections, and severe mucocutaneous lesions. Patients in the fourth stage have severe symptoms of various diseases that define AIDS (pneumocystis pneumonia, severe bacterial pneumonia, extrapulmonary tuberculosis, HIV encephalopathy, chronic toxoplasmosis, orolabial herpes, Kaposi’s sarcoma). In addition, other severe or protracted infections should prompt preforming diagnostics for HIV [22].

Women infected with HIV more often have pathological changes of the cervix caused by the human papillomavirus, vaginal candidiasis, and pelvic inflammatory disease. HIV infection also negatively affects fertility [23].

THE IMPACT OF HIV ON THE MOTHER AND FETUS

In areas with poorer economic conditions, tuberculosis is the most common opportunistic infection in pregnant women with HIV [24]. In addition to tuberculosis, pneumonia caused by the fungus Pneumocystis Jirovecii and parasitic infections are common during pregnancy and the puerperium [11]. The negative impact of HIV on the frequency and course of many infections in pregnancy, such as genital herpes, human papillomavirus infection, vulvovaginal candidiasis, bacterial vaginosis, syphilis, trichomoniasis, toxoplasmosis, malaria, hepatitis B and C virus infection, as well as cytomegalovirus. HIV-infected pregnant women also have more frequent urinary tract infections and bacterial pneumonia [11].

Table 1. Factors associated with risk of perinatal HIV transmission [25].

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The impact of HIV on the fetus depends on the stage of HIV infection in the mother, the concentration of viral ribonucleic acid (RNA) in the plasma and the number of CD4+ T lymphocytes of the mother, as well as the time of rupture of the fetal membranes. If the mother has associated and other sexually transmitted diseases, the genital secretion of HIV is increased [23].

Pregnancy complications in case of HIV infection include an increase in perinatal morbidity and mortality, namely: more frequent miscarriages, chorioamnionitis, intrauterine growth retardation, low birth weight and stillbirth [26].

It is considered that pregnancy does not negatively affect the course of HIV infection, in terms of disease progression, or shorter survival of the mother. Stable values of viral RNA during pregnancy have been diagnosed, but a decrease in the number of CD4+ T lymphocytes is possible, which has been explained by hemodilution rather than by a real decrease in the number of blood cells [27]. The data refer to developed countries, while in underdeveloped countries, especially in sub-Saharan Africa, significant morbidity and mortality have been observed in HIV-infected mothers, and not only in time periods when antiretroviral therapy was less available [3],[28].

DIAGNOSTICS OF HIV INFECTION IN PREGNANCY

The diagnosis of HIV infection can be made indirectly – by detecting anti-HIV antibodies. HIV-specific IgG class serum antibodies are proven by enzyme-linked immunosorbent assay (ELISA). Confirmation by Western blot analysis is necessary. The first tests for the detection of anti-HIV antibodies appeared in 1984, and since 1985, mandatory testing of blood used for transfusion for HIV has been in place [29]. There are also rapid tests for proving anti-HIV antibodies, which have high specificity and sensitivity, and are most often used to diagnose infection during childbirth in women with unknown HIV status.

Tests for proving virus particles are used to confirm the presence of protein particles, e.g., p 41, or viral genetic material.

Viral nucleic acids (ribonucleic – RNA or proviral deoxyribonucleic – DNA) are proven by polymerase chain reaction (PCR). There is a period of time (the window period) between exposure to HIV and a positive test, because it takes time for the virus to sufficiently replicate in the host, or for the host to initiate an immune response to the infection that can be detected. When detecting anti-HIV antibodies with latest generation tests, this period is 11 days. It is similar when the PCR method is applied, where the window period is 12 days [30]. In infants of HIV-infected mothers, anti-HIV antibodies originating from the mother can persist until the eighteenth month of life, so their determination during that period cannot rule out infection.

FOLLOW-UP AND TREATMENT OF HIV INFECTION IN PREGNANCY

Follow-up of pregnant women infected with HIV is necessary because of the possible progression of HIV infection and because of the effect of the applied antiretroviral therapy. To assess the stage of HIV infection in pregnancy, physical examination methods and various microbiological methods are applied, so as to verify opportunistic infections. In addition, hematological (complete blood count, reticulocytes, serum iron), biochemical (tests for kidney, liver, pancreatic function), and immunological tests (number of CD4+ T lymphocytes) are used. The stages of HIV infection, in addition to clinical indicators, are determined based on the number of CD4+ T lymphocytes. The progression of the disease is accompanied by a decrease in the number of these cells. On the other hand, their increase is an indicator of immune reconstitution during the administration of antiretroviral therapy. Pregnant women with newly discovered HIV infection do not require additional tests, except those that are routinely performed. It is important to monitor the HIV viral load, at least once in each trimester and immediately before delivery [31].

In order to reduce the risk of transmission of the virus from the mother to the fetus, it is preferable to start the treatment of HIV infection before the planned pregnancy [5]. Considering that antiretroviral drugs are eliminated through the liver and kidneys, it is necessary for the function of these organs to be monitored in pregnant women during treatment. One of the side effects of the therapy can be bone marrow suppression, so regular monitoring of the blood count is also necessary [32]. Antiretroviral therapy is adapted to the HIV genotype, which is determined before starting therapy. As with other HIV-infected persons, the presence of hepatotropic viruses B and C is also investigated in pregnant women [32]. Table 2 shows the follow-up protocol for pregnant women with HIV infection [30].

Table 2. Follow-up of HIV infection in pregnancy [30]

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Non-invasive screening tests should be used in pregnancies with risk of fetal chromosomal aberrations [32]. If not necessary, all invasive tests should be delayed until the viral load is < 50 copies of HIV RNA/ml of serum. If invasive diagnostics is still necessary, antiviral therapy must be administered 2 – 4 hours before the procedure [32]. Data from literature indicate that amniocentesis is safe in women taking antiretroviral therapy [33].

The only antiretroviral drug officially approved for use in pregnancy is zidovudine, which can be used in the third trimester. However, there is a global consensus that women who have been treated before pregnancy should continue the treatment during pregnancy and for life. Drugs can be changed in relation to previous treatment, depending on their pharmacokinetics in pregnancy [31]. The goal of therapy is to maintain the lowest possible viral load, especially at the time of delivery, in order to reduce the risk of vertical transmission. The World Health Organization recommends that all pregnant and breastfeeding women with HIV, regardless of the viral load, CD4+ T lymphocyte count, and clinical stage of infection, should be treated [34]. It is recommended that the treatment of pregnant women who were not treated with antiretroviral therapy before pregnancy should be started in the early second trimester of pregnancy [31]. The choice of drugs depends on their toxicity, the length of treatment, the resistance of the virus, and the presence of comorbidities. Attention should also be paid to the frequency of dosing and interactions with other drugs. It is of great importance that the drug can cross the placental barrier and provide pre-exposure prophylaxis [31].

Toxicity of antiretroviral drugs is common. It usually manifests as anemia, mitochondrial disorders (myopathy, peripheral neuropathy, cardiomyopathy), hyperlipidemia, insulin resistance. Bone structure disorders (osteopenia, osteoporosis) and skin lesions have also been registered [35],[36]. Despite the high frequency of side effects of antiretroviral therapy observed in pregnant women, there have been no severe side effects registered. Newer generation drugs are expected to have better efficacy and a significantly more favorable tolerability profile [37].

The teratogenic effects of antiretroviral therapy are still the subject of investigation, especially due to the development of new drugs. The potential impact on the fetus depends on the drug itself, the dosage, the gestational age of the fetus at the time of exposure to the drug, the length of therapy, and the interaction of the drug with other agents to which the fetus is exposed. Available information is based on in vitro and in vivo animal tests, but the predictive value of such tests in the human population is unknown [38]. Based on the data from the American National Guide, it can be concluded that the occurrence of congenital malformations is 1.5 times more frequent in newborns whose mothers took antiretroviral therapy in the first trimester. A limiting factor in this study was that the sample included only 1,000 infants [38]. The role of antiretroviral therapy in the development of congenital malformations remains controversial. Birth defects of the genitourinary and cardiovascular systems are most often mentioned [39]. In several studies of congenital anomalies in fetuses and infants of women receiving different antiretroviral drugs, no difference was observed in relation to drug exposure in the first and subsequent trimesters [40],[41],[42].

DELIVERY IN HIV INFECTED WOMEN

The goal of antiretroviral therapy during pregnancy is to keep the HIV viral load as low as possible at the time of delivery. If the level is < 50 copies of HIV RNA/ml of blood in the 36^th week of pregnancy and if there are no obstetric contraindications, vaginal delivery is the preferred option. If there are 400 copies of HIV RNA/ml in the pregnant woman’s serum in the 36^th week, the delivery should be performed by elective caesarean section. For women with a viral load of 50 - 399 copies of HIV RNA/ml, caesarean section should be considered while also taking into account the monitoring of the viral load throughout the pregnancy, the duration of treatment, obstetric factors, and the opinion of the pregnant woman. Also, it is important to note the conclusion drawn in previous research stating that the risk of vertical transmission of HIV is twice as high in vaginal delivery, as compared to caesarean section [31],[43]. In order to reduce the probability of virus transmission during cesarean section, it is recommended to perform it between the 38^th and 39^th week of gestation [44].

If an HIV-infected pregnant woman gives birth vaginally, the delivery should, if possible, be carried out according to the protocol for pregnant women who are not infected with HIV. Earlier recommendations to avoid amniotomy, instrumental delivery, episiotomy and fetal blood sampling are no longer considered valid, due to the use of antiviral therapy, which has greatly reduced the risk of vertical transmission of the virus [5]. The data show that the use of instruments during childbirth is not as risky for the transmission of infection as previously believed. The choice of the type of operative delivery should always ensure the least trauma to the fetus [45]. After the rupture of the fetal membranes, the delivery should be completed within 24 hours. There are data in literature indicating that during this period there is no increased risk of virus transmission [46].

In order to reduce the risk of HIV transmission from mother to the neonate during childbirth, the use of delayed umbilical cord clamping, of one to three minutes, has been investigated as a possible risk factor [47]. Delayed umbilical cord clamping is a method to reduce the risk of anemia in the newborn baby [48]. Literature data have not shown that delaying umbilical cord clamping increases the possibility of mother-to-newborn HIV transmission. Due to the proven benefits of delaying umbilical cord clamping, between one and three minutes, this is also recommended to be applied in deliveries of women living with HIV, or women with an unknown HIV status [47].

PREVENTION OF HIV INFECTION DURING PREGNANCY IN SERODISCORDANT COUPLES

Serodiscordance means that one partner has the HIV infection while the other does not. Quite often, such couples are looking for a mode of conception that would be safe for the uninfected partner and that would result in the lowest possible risk of vertical transmission of the virus to the offspring. Serodiscordant couples should be treated before the planned pregnancy, in order to minimize the risk of transmission of infection, both to each other and to the fetus. This implies the use of antiretroviral therapy for the HIV-infected partner and the use of daily pre-exposure prophylaxis (PrEP) for the non-infected partner [49].

In infected women, in HIV serodiscordant couples, intrauterine insemination, with or without ovulation stimulation, with proper condom use, can reduce the risk of HIV transmission, when the man is HIV-uninfected [50].

If the man is infected, the application of antiviral therapy can lead to a notable change in sperm quality and a consequent reduced possibility of conception [51]. Since 1992, sperm processing methods have been initiated to achieve conception with the lowest risk of viral transmission [52]. The use of advanced sperm processing techniques combined with intrauterine insemination or in vitro fertilization using intracytoplasmic sperm injection, has been shown to be highly effective in preventing virus transmission to an uninfected female partner and fetus [53].

PrEP involves chemoprophylaxis, i.e., the use of specific antiretroviral drugs to prevent HIV infection. The use of the combination of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), as daily oral PrEP to reduce HIV infection, was approved by the United States Food and Drug Administration (FDA) in 2012 [54]. Indications for PrEP include risk factors for acquiring HIV, such as unprotected sex with an HIV-positive partner or intravenous drug use. When taken as prescribed, TDF/FTC provides protection against HIV infection of more than 90% [55].

It is considered that women who become pregnant while using TDF/FTC as PrEP may continue with PrEP throughout their pregnancy. This is based on a study that examined PrEP for HIV in a population of HIV-negative women taking placebo or TDF/FTC. There was no difference regarding the risk of congenital anomalies between these groups [56].

CONCLUSION

HIV infection affects both the pregnant woman and the fetus, therefore, careful antenatal, intrapartum, and postpartum follow-up is important. The main goals of monitoring and treating HIV infection during pregnancy are the prevention of transmission of the virus to the fetus, the preservation of the mother’s health, and the provision of conditions for a safe delivery for both mother and child. In relation to this, the existence of a national guide is of foremost importance.

A multidisciplinary approach is necessary for adequate monitoring of a pregnant woman with HIV infection. The decision on antiretroviral therapy, as well as on the time and mode of delivery, should be individual for each pregnant woman, and is made based on the HIV viral load, the mother’s clinical presentation of HIV infection, and the condition of the fetus.