HIV infection in pregnant women

Human immunodeficiency virus (HIV) is an anthroponotic infection characterized by progressive damage to the immune system, leading to the development of acquired immunodeficiency syndrome (AIDS) and death from secondary diseases. The pathogen belongs to the family of retroviruses (Retroviridae), subfamily of slow viruses (Lentivirus).

Epidemiology

HIV infection among pregnant women has become a global public health problem with significant health, economic and social consequences. In 2019, an estimated 19.2 million women were living with HIV, representing 52% of all adults living with the infection. HIV infection during pregnancy has become the leading cause of death among women of reproductive age. [ 1 ] Although pregnancy itself contributes little to HIV progression in asymptomatic women or women with early infection, 4 it poses significant risks to infants, families and health care workers. [ 2 ]

In the absence of antiretroviral therapy (ART) or prophylaxis, the risk of mother-to-child transmission of HIV is approximately 15–20% in Europe, 15–30% in the United States (US), and 25–35% in Africa ( MTCT Working Group, 1995, Volmink et al., 2007 ). Although these transmission rates have improved with the introduction of antiretroviral therapy for the prevention of mother-to-child transmission (PMTCT), only a minority of women receive PMTCT (WHO, 2008).

Pathogenesis

HIV infection can occur in the following ways:

• sexual (during heterosexual and homosexual contacts);
• injection (when drugs are administered using shared needles and syringes);
• instrumental (when using non-sterilized medical instruments: endoscopes, surgical instruments, gynecological mirrors, dental drills, as well as gloves, etc.);
• hemotransfusion (during transfusion of infected donor blood or its components);
• transplantation (during transplantation of donor organs, artificial insemination with sperm from a donor who is in the seronegative “window” period);
• professional (infection of healthcare workers through damaged skin and mucous membranes upon contact with infected blood or other secretions of HIV-infected people);
• perinatal (vertical - transmission from mother to child during pregnancy and childbirth, horizontal - during breastfeeding, as well as transmission of HIV from an infected child to a healthy woman who is breastfeeding him).

The main routes of infection spread in the world are sexual, injection and perinatal.

Transmission of the virus from an infected mother to her child can occur:

• antenatal (transplacental, through the amniotic membranes and amniotic fluid, during diagnostic invasive manipulations);
• intrapartum (during childbirth);
• postnatally (during breastfeeding).

Intrauterine HIV infection can occur at any stage of pregnancy: HIV has been isolated from tissues of 10-15-week abortions, amniotic fluid in the first and second trimesters of pregnancy, and from placental tissue after full-term births. Evidence of intrauterine transmission (starting from the 8th week of pregnancy) may include detection of HIV-1 and viral antigens (p24) in fetal samples and placental tissue; isolation of the virus in some infected infants at birth, which suggests its transmission before birth; the fact that the disease develops very early in some infected newborns, suggesting that they acquired the infection in utero. When the embryo is infected in the first trimester, pregnancy most often terminates spontaneously, and when infected at a later stage, it is prolonged. Intrauterine infection occurs mainly in the late stages of pregnancy, shortly before delivery.

However, the most common time for HIV transmission is during childbirth. This conclusion is based on the absence of HIV-associated dysmorphism syndrome and manifestations of HIV infection at birth, as well as the observation that 50% of children who are not diagnosed with HIV in the first week of life are actually infected when tested later. Breastfeeding accounts for about 20% of all cases of infection in children.

Every year, approximately 600–800 thousand newborns are infected by sick mothers worldwide; the total number of children with HIV/AIDS has exceeded 3 million; approximately 500 thousand children die from HIV/AIDS every year.

The rate of perinatal transmission of HIV varies:

• from 24 to 40% in developing countries with breastfeeding and no other preventive measures;
• from 2 to 10% in developed countries when implementing a range of preventive measures.

The reason why vertical transmission of HIV infection does not always occur is the complexity and diversity of factors that contribute to the transmission of the virus from mother to child. These are various pathological conditions of the mother and fetus, disruption of the protective function of the placenta, and the peculiarities of the course of labor.

Of course, the general health of the mother is important. Drug and alcohol use, promiscuous sex during pregnancy, and poor nutrition have a negative effect. The risk of perinatal infection increases in the acute stage of HIV infection and disease progression, when a high level of viremia is observed - more than 10,000 copies in 1 μl. It has been shown that more than half of women transmitted the infection with a viral load of more than 50,000 copies in 1 μl. The risk increases with a decrease in the number of CD4 lymphocytes to less than 500 in 1 μl of blood, as well as in the presence of extragenital pathology in the mother (kidney disease, cardiovascular disease, diabetes mellitus) and sexually transmitted diseases.

The genotype and phenotype of the virus are of certain importance. A number of HIV-1 subtypes with different geographical distribution zones have been established. In case of HIV-2 infection, the frequency of vertical transmission is significantly lower.

Of great importance is the condition of the placenta, its integrity, the presence of cell damage and the sensitivity of cells to the virus. A correlation has been proven between an increase in the frequency of HIV transmission and the presence of chorioamnionitis, placental insufficiency, as well as in the case of premature placental abruption and bleeding.

It is necessary to take into account the gestational age of the fetus at birth: infection of premature babies is higher. HIV infection can be the cause of premature birth in case of antenatal infection. During childbirth, a premature baby is also exposed to a higher risk due to the immaturity of the immune system. Violation of the integrity of the skin and mucous membranes of the newborn is an additional risk factor.

Anomalies of labor, duration of labor more than 12 hours, anhydrous period more than 4 hours, a large number of vaginal examinations, the use of amniotomy, episiotomy, perineotomy, application of obstetric forceps, monitoring using invasive methods during labor increase the likelihood of virus transmission.

[ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ], [ 11 ]

Forms

Classification of HIV infection

According to the classification of V.I. Pokrovsky (created in 1989, modified in 2001), the following stages of HIV infection are distinguished:

1. The incubation stage is the period from the moment of infection until the appearance of signs of acute infection and/or the production of antibodies.
2. The early stage of HIV infection is the body's primary response to the introduction of the pathogen in the form of clinical manifestations and/or antibody production. Course options:
   • asymptomatic seroconversion;
   • acute HIV infection without secondary manifestations.
3. Subclinical stage - slow progression of immunodeficiency with a gradual decrease in the level of CD4 lymphocytes, moderate viral replication and minor lymphadenopathy.
4. The stage of secondary diseases is the ongoing replication of HIV, leading to the death of CD4 lymphocytes and depletion of their population, the development of secondary (opportunistic), infectious and/or oncological diseases against the background of immunodeficiency. Depending on the severity of secondary diseases, stages IVA, IVB, IVB are distinguished.
5. Terminal stage - secondary diseases become irreversible, the therapy does not produce results, patients die within a few months. In adults, the time from infection to the appearance of clinical manifestations of the disease is usually 2-4 weeks, but cases of a longer incubation period have been described - up to 10 months.

Seroconversion—the appearance of antibodies to HIV—occurs within 3–12 weeks after infection.

The duration of the stage of primary clinical manifestations is 5–44 days (in 50% of patients 1–2 weeks).

The latent period following the stage of primary clinical manifestations can last for many years (from 2 to 20 years or more).

According to the definition of the US Center for Disease Control, AIDS is diagnosed in patients who have antibodies to HIV, with a CD4 lymphocyte count of less than 200 per 1 μl and the presence of one of the AIDS-indicating diseases. The most common AIDS-indicating diseases in our country are:

• tuberculosis;
• candidiasis of the esophagus, trachea, bronchi and lungs;
• cytomegalovirus infection;
• Kaposi's sarcoma;
• Pneumocystis pneumonia;
• toxoplasmosis.

Highly active antiretroviral therapy can stop the natural progression of the infection. By improving the immune status, opportunistic infections are prevented or cured, and life expectancy of patients is increased. However, not all patients receiving antiretroviral therapy respond to treatment: they may have progression of the disease with the development of secondary and opportunistic diseases.

HIV infection can occur in the following ways:

• sexual (during heterosexual and homosexual contacts);
• injection (when drugs are administered using shared needles and syringes);
• instrumental (when using non-sterilized medical instruments: endoscopes, surgical instruments, gynecological mirrors, dental drills, as well as gloves, etc.);
• hemotransfusion (during transfusion of infected donor blood or its components);
• transplantation (during transplantation of donor organs, artificial insemination with sperm from a donor who is in the seronegative “window” period);
• professional (infection of healthcare workers through damaged skin and mucous membranes upon contact with infected blood or other secretions of HIV-infected people);
• perinatal (vertical - transmission from mother to child during pregnancy and childbirth, horizontal - during breastfeeding, as well as transmission of HIV from an infected child to a healthy woman who is breastfeeding him).

HIV Infection in Pregnant Women - Epidemiology

[ 12 ], [ 13 ], [ 14 ], [ 15 ]

Diagnostics HIV infections in pregnant women

Diagnosis of HIV infection includes 2 stages:

• establishing the actual fact of HIV infection;
• determination of the stage, nature of the course and prognosis of the disease.

The diagnosis is established on the basis of a comprehensive assessment of epidemiological data, clinical examination results and laboratory tests.

Laboratory research

• Enzyme immunoassay is a screening test that detects HIV antibodies in blood serum, and is performed during voluntary testing, in conjunction with diagnostic testing of patients, and also according to clinical indications. In case of a positive result, the analysis in the laboratory is performed twice (with the same serum), and if at least one more positive result is obtained, the serum is sent for a confirmatory test.
  • The earliest detection of antibodies is 2 weeks from the moment of infection.
  • In 90–95% of patients, antibodies appear within 3 months.
  • In 5–9% of patients – after 6 months.
  • In 0.5–1% of patients – at a later date.
• It is important to remember that a negative enzyme immunoassay result is observed in a recently infected person who is in the so-called “window” period, but is already a source of infection.
• Immunoblotting is a method for checking the specificity of the results of enzyme immunoassay. The principle of the method is to detect antibodies to certain viral proteins. Until a positive result is obtained and with a negative result of this test, a person is considered healthy.
• Polymerase chain reaction (PCR) is used to clarify the prognosis and severity of HIV infection. It allows determining the viral load - the number of copies of HIV ribonucleic acid (RNA) in the blood serum.

The viral load indicator is used to quickly assess the effectiveness of antiretroviral therapy. A significant change in the concentration of HIV RNA is considered to be a difference of at least 3 times. With effective antiretroviral therapy, a decrease in the level of HIV RNA by 3-5 times is noted by the 4th to 8th week. By the 12th to 16th week, the level of HIV RNA becomes undetectable in most patients.

PCR is successfully used to diagnose HIV infection in children born to HIV-infected mothers, since maternal antibodies, determined by enzyme-linked immunosorbent assay, circulate in children up to 18 months of age.

The advantage of PCR is that it allows detection of the virus during the incubation and early clinical periods, when antibodies may not be present.

In addition to specific diagnostic methods, immunological methods are used to determine the stage of the disease based on:

• total lymphocyte count;
• the number of T-helpers (CD4);
• the number of T-suppressors (CD8);
• immunoregulatory index - CD4/CD8 ratio.

In most healthy adults, the minimum CD4 lymphocyte count is about 1400/μL.

• A decrease in the number of T-helpers to 500 in 1 μl indicates developing immunosuppression, and in the AIDS stage there may be less than 200.
• The content of T-helpers is an important prognostic sign: the risk of developing AIDS and death in the next 24 months in patients with a CD4 lymphocyte count of less than 500 in 1 μl is 5%, and in individuals with a count of less than 50 in 1 μl - 70%.
• The level of T-helpers helps to assess the need for antiretroviral therapy, and an increase in the content of T-helpers 1 month after the start of therapy is considered a criterion for its effectiveness.
• The CD4/CD8 ratio in healthy people is 1.8–2.2, and a decrease in this ratio indicates immunosuppression.

When diagnosing HIV infection, the stage of the disease is always indicated and a detailed explanation of secondary diseases is given.

According to accepted standards of medical care, pregnant women are tested for the first time when they register for pregnancy (at their first visit), and the second time - at 30-32 weeks of pregnancy. In some maternity hospitals, a third test is performed when a woman is admitted to labor.

[ 16 ], [ 17 ], [ 18 ], [ 19 ]

Differential diagnosis

A double study using enzyme immunoassay followed by confirmation of the result in immunoblotting allows for the diagnosis of HIV infection to be established with almost 100% certainty.

Treatment HIV infections in pregnant women

The main goal of treatment of patients with HIV infection is to prolong life with maximum preservation of its quality.

Basic principles of treatment

• Creation of a protective psychological regime.
• Timely initiation of effective antiretroviral therapy and prevention of secondary diseases.
• Careful selection of the required minimum of medicines.
• Early diagnostics and timely treatment of secondary diseases. For the treatment of HIV infection and AIDS, drugs of the following groups are used:
  • HIV reverse transcriptase inhibitors;
  • HIV protease inhibitors;
  • drugs from the group of interferon inducers, which have non-specific antiviral activity.

Features of antiretroviral therapy during pregnancy

There are 2 main groups of indications for antiretroviral therapy in pregnant women:

• antiretroviral therapy for HIV infection;
• chemoprophylaxis of perinatal transmission of HIV.

This is fundamentally important because antiretroviral therapy for HIV infection should be considered as therapy administered for vital indications. When deciding on its administration, it is necessary to observe the principle of the priority of preserving the life of the mother over preserving the fetus.

Chemoprophylaxis of perinatal transmission of infection is carried out in the interests of the fetus, since the mother's condition at this time does not require the use of antiretroviral drugs.

In some cases, treatment of HIV infection in the mother also serves as prevention of infection of the fetus.

Treatment options depending on a woman's HIV status

1. When HIV infection is detected in the early stages of pregnancy (first trimester), if the woman plans to continue the pregnancy, the question of starting therapy is extremely difficult due to the likelihood of embryotoxic and teratogenic effects, but with a high viral load, a delay in prescribing antiretroviral therapy will worsen the prognosis of the disease in the mother and increase the risk of infection of the fetus. Therefore, in such cases, it is advisable to offer the woman to terminate the pregnancy.

Indications for antiretroviral therapy are determined taking into account:

• stages of HIV infection;
• CD4 lymphocyte level;
• number of virus copies;
• pregnancy period.

If the pregnancy period is up to 10 weeks, treatment should be started:

• in stage IIA, IIB and IIB with a viral load above 100,000 copies in 1 ml;
• in stages III and IVA with a CD4 count of less than 100 in 1 μl, viral load above 100,000 copies in 1 ml;
• in stage IVB, regardless of the CD4 count and viral load level.

If treatment is carried out in the first 14 weeks of pregnancy, regimens that include didanosine and phosphazide are preferable - drugs that are the least dangerous for the fetus during this period.

Of the protease inhibitors, nelfinavir is preferred. Theoretically, all currently known protease inhibitors may increase the risk of diabetes or at least hyperglycemia in pregnant women. Therefore, pregnant women receiving protease inhibitors should be instructed regarding the symptoms of hyperglycemia. Blood sugar monitoring should be performed at least once every 2 weeks.

If pregnancy occurs while treatment is already underway, it is recommended to continue it if the HIV infection is in stages IIB, IIB, IVB and IVB.

In this case, it is necessary to take into account the risk to the fetus and adjust treatment regimens. The woman must be explained the high probability of teratogenic effects of drugs used in the early stages of embryogenesis. The best option in this situation should be considered termination of pregnancy.

When continuing previously prescribed therapy, it is recommended to replace zidovudine or stavudine with phosphazide, and zalcitabine or lamivudine with didanosine.

The intensity of therapy is determined based on the available clinical, immunological and virological indications and data on the specific effects of drugs on the body of the pregnant woman and the fetus.

In more favorable stages of the disease, if the CD4 lymphocyte level is at least 200 in 1 μl, the treatment should be interrupted before the end of the 13th week of pregnancy. However, if the disease progresses during this period, the treatment should be resumed.

It is important to keep in mind that in case of a planned pregnancy, the use of antiretroviral drugs should be stopped before the woman's fertile menstrual cycle begins to avoid embryotoxic effects. Stopping the drugs after a missed period is less effective, since the processes of early embryogenesis have already been completed.

Chemoprophylaxis of mother-to-child transmission of HIV

To reduce the risk of HIV transmission from mother to child during childbirth, several chemoprophylaxis regimens have been developed:

1. Zidovudine regimen: chemoprophylaxis begins at 28 weeks of pregnancy. If HIV infection in a pregnant woman was detected at a later stage, chemoprophylaxis begins as early as possible (from the moment of diagnosis):
   • zidovudine orally 200 mg 3 times a day for the entire duration of pregnancy;
   • in case of intolerance - phosphazide 200 mg 3 times a day for the entire duration of pregnancy.
2. Scheme with nevirapine: 0.02 g tablet once at the onset of labor (if the patient received zidovudine during pregnancy, it is not stopped until the end of labor).

Scheme with intravenous administration of zidovudine: in the form of a solution for intravenous administration, it is prescribed at the onset of labor. Within 1 hour, it is administered at a rate of 0.002 g / kg, then (if necessary) - at a rate of 0.001 g / (kg × h) until the end of labor.

The nevirapine regimen is simpler to use and cheaper. In addition, the addition of a new drug, nevirapine, helps overcome resistance to zidovudine, which can develop with prolonged use during pregnancy. The intravenous zidovudine regimen is recommended for use primarily in patients who did not receive the drug during pregnancy, as well as in patients who previously received nevirapine.

In addition, so-called backup schemes are proposed. They are recommended if it is impossible for some reason to use one of the main schemes.

Oral zidovudine regimen: 0.3 g at the onset of labor, then 0.3 g every 3 hours until delivery.

Phosphazide regimen: 0.6 g orally at the onset of labor, then 0.4 g every 4 hours. If the patient received zidovudine during pregnancy, it should be discontinued.

Evaluation of treatment effectiveness

The criterion for the effectiveness of chemoprophylaxis is the prevention of infection in the child.

Chemoprophylaxis can reduce the likelihood of a child becoming infected by 3-4 times. However, it is currently impossible to completely protect a child from HIV transmission.

When carrying out chemoprophylaxis, control examinations are necessary, the purpose of which is:

• assess how well the pregnant woman adheres to the medication regimen;
• assess safety (identify side effects of chemotherapy drugs);
• assess the course of HIV infection;
• identify indications for prescribing antiretroviral therapy.

The first scheduled examination is performed after 2 weeks, the second - after 4 weeks from the start of chemoprophylaxis, then every 4 weeks. All examinations include patient counseling and physical examination. At each control examination, it is necessary to conduct a blood test to determine the level of hemoglobin, red blood cells, platelets, and white blood cell count. At the end of the 4th, 8th, 12th and 20th week of therapy, as well as 4 weeks before the expected date of delivery, the level of CD4 lymphocytes is determined.

After 4 and 12 weeks of chemoprophylaxis and 4 weeks before the expected date of delivery, the viral load is determined. If the CD4 lymphocyte level is below 300 in 1 ml or the viral load is more than 30,000 copies in 1 ml, it is recommended to repeat these studies after 2 weeks and, if the same results are obtained, to begin high-intensity antiretroviral therapy. It should also be started according to clinical indications if the patient develops secondary diseases associated with HIV infection.

Side effects of treatment

The safety of most antiretroviral drugs for the fetus has not been proven during the first 13 weeks of pregnancy.

The absence of toxic effects on the fetus in animal experiments has been demonstrated for didanosine, zidovudine, lamivudine, nevirapine, nelfinavir and saquinavir, but clinical trials have not been conducted.

Experimental studies on animals have shown that indinavir, efavirenz can potentially be dangerous for the fetus in the first trimester of pregnancy. Efavirenz is the most toxic to the fetus.

The most common serious complications of zidovudine therapy are anemia, granulocytopenia and (less commonly) thrombocytopenia.

Due to the pronounced toxic effect on the fetus, women who plan to continue the pregnancy should not be prescribed treatment regimens containing efavirenz and indinavir. If treatment is already carried out with these drugs, they should be replaced with analogues.

Forecast

To date, there is no possibility of complete cure for patients with HIV infection. The average duration of the disease from the moment of HIV-1 infection to death is 11-13 years. Some patients, especially those leading an asocial lifestyle, die much earlier, while some individuals live 15 years or more from the moment of infection.

[ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ]