HIV in Cuba:
Prevention of Mother-to-Child Transmission
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SPOTLIGHT

National Program for Detecting & Treating
Mother-to-Child Transmission of HIV

By Ida González Núñez MD, PhD
Manuel Díaz Jidy MD
Jorge Pérez Ávila MD, MS
Héctor L. Mengana Gutiérrez, MD
Ida Gutiérrez, MD
Conner Gorry 


INTRODUCTION

Cuba’s health system provides free counseling and prevention coverage to all women diagnosed  with HIV, one reason why so few infants have been infected by their mothers:  since 1986 and through October 2005, 26 cases of such vertical transmission have been recorded out of 214 live births to HIV+ women (12%). Additionally, antiretroviral treatments are made available to both seropositive pregnant women and their babies, safe delivery practices are indicated, breastfeeding substitutes are advised along with meticulous follow-up and nutritional dietary supplements.

By comparison, 35% of women worldwide infect their children when no preventive measures are taken, with only  8.7% of HIV+ mothers-to-be worldwide receiving prevention coverage, according to UNICEF (2004).

From HIV testing for all pregnant women to exact antiretroviral dosages for HIV+ infants, the following outlines the guidelines offered by Cuba’s national program for preventing, detecting and treating mother-to-child transmission of the human immunodeficiency virus in Cuba, as well as the national follow-up program for children born to seropositive mothers. 

VERTICAL TRANSMISSION

Disease-causing agents transmitted from mother to baby during pregnancy or the perinatal period (i.e. vertically-transmitted pathogens) account for a variety of infant health problems. This has prompted the establishment of health prevention and control programs worldwide, including vaccination campaigns, health education projects, and early detection of infections, congenital ones, as well during pregnancy. Additionally, Cuba has created a nationwide registry of cases, and performs routine serological screenings of pregnant women for the detection of antibodies and/or antigens of specific pathogens.

Major Vertically-Transmitted Infectious Agents

  • Human cytomegalovirus (CMV) and Toxoplasma gondii: Fetal infection can occur during the acute phase of the mother’s primary infection, when the virus or the parasite is in her bloodstream. In the case of CMV, whose latency and recurrence mechanisms are only partially known, congenital and neonatal infection associated with recurrent infection is common. However, it seldom has an impact on neonate health.

  • Hepatitis B (HBV), Human Immunodeficiency Virus (HIV) and Treponema pallidum: These persistent or chronic infections can pass from mother to fetus or newborn, through contact with the mother’s blood or bodily fluids.

  • Herpes simplex virus (HSV, in particular HSV type 2, HSV-2): This virus causes a recurrent chronic infection of the sacral sensory nerve ganglia. It can pass from mother to baby during childbirth through contact with viruses present in the mother’s cervical and vaginal herpetic lesions, if a few days before labor the viruses lying dormant in the sensory nerve ganglia of the nearby nerves have been reactivated, causing a recurrent episode of herpes infection.

Each of these three modes of transmission calls for specific prevention strategies and serologic screening criteria.

Infections included in the first group above require identification of women susceptible to primary infection (women seronegative for specific antibodies) and for measures to prevent them from coming into contact with these infectious agents during pregnancy.

Infections in the second group require using specific serological markers to detect those women with persistent or chronic infections. The necessary measures to prevent transmission, or palliate the effects of newborn infection, are also specific to each infectious agent.

To prevent infections in the third group, women with recurrent infections presenting transmission risk must be identified, including the timing and location of lesions. In the case of HSV-2, it should be ascertained whether viruses are present in the cervix and vagina in the days prior to delivery since in this case, control cannot be carried out through serological studies.

In the case of CMV, it isn’t yet possible to define an effective prevention strategy. It is important to emphasize that the detection of antibodies against these viruses is of no use for the prevention of recurrent infections. Only the detection of specific antibodies against HSV-2 could help identify those women in whom an effective control of the viral discharge through their genitalia can be achieved. At present, the serologic techniques available do not allow this.

Serologic Screening Programs for Pregnant Women

The following infectious agents are recommended for inclusion in the serologic screening programs for all pregnant women (except for rubella which has been eradicated, these tests are standard in Cuba):

  • Rubella virus
  • Toxoplasma gondii
  • HVB
  • Treponema pallidum
  • HIV


First Visit to the Obstetrician/Family Doctor

The patient’s physical examination and medical history should search for:

  • Recent febrile disease or exanthema
  • Acute or chronic hepatitis
  • Genital herpes
  • Multiple genital infections
  • Recent close contact with people with exanthema
  • Professional contact with children
  • Previous rubella and hepatitis B vaccination
  • Previous checks for antibodies against the rubella virus or Toxoplasma gondii
  • High risk behavior for HIV infection

Ensure that there is no:

  • Exanthema, with or without fever
  • Adenopathy (in any region of the body)
  • Genital herpes lesions
  • Syphilitic lesions (any stage)

The following tests should be performed:

  • Qualitative determination of IgG antibodies against the rubella virus and Toxoplasma gondii, to identify seronegative women.
  • Qualitative determination of hepatitis B surface antigen (HbsAg).
  • Qualitative determination of antibodies against non-treponemal antigens related to Treponema pallidum.
  • Qualitative determination of antibodies against HIV where high risk behavior for HIV infection is known or suspected.

Reproductive Health Advice

A health care professional’s main responsibility to pregnant women found to have HIV is to offer emotional and medical support. These women have several options: they can continue their pregnancy without medication; continue their pregnancy with antiretroviral drugs such as zidovudine; or they can interrupt their pregnancy.  

Topics to discuss with these women include:

  • The effects of HIV on their pregnancy
  • The risk of transmitting HIV to their babies
  • How to reduce the risks of HIV transmission
  • The prognosis for babies who contract HIV
  • Pros and cons of antiretroviral therapy
  • Alternatives to breastfeeding

Prevention of Mother-to-Child Transmission of HIV

Research shows several factors associated with a higher risk of mother-to-child transmission of HIV.

Maternal factors:

  • Nutritional deficiencies
  • Recent HIV infection - women infected with HIV in the two or three months prior to their pregnancy are at a greater risk of passing the virus to their baby
  • Advanced HIV infection or AIDS
  • Low CD4+ count
  • High viral load
  • Serum presence of the p24 antigen (a component of HIV)
  • Some STI (herpes, syphilis, chancroid)
  • Lack of access to antiretroviral drugs such as zidovudine (AZT)

Obstetric factors:

  • Premature labor (before the 37th week of pregnancy)
  • Premature membrane rupture, the risk being higher when the membrane has been ruptured for over four hours
  • Inflammation of placental membranes
  • Use of instruments during labor or at childbirth

Postpartum factors:

  • Breastfeeding
  • Duration of breastfeeding
  • Breast disorders such as cracked, bleeding nipples

Antiretroviral Therapy

In women who have not taken antiretroviral drugs, treatment can be initiated at any time after the 14th week of pregnancy, even at labor. The treatment regime most commonly used is the ACTG 076 protocol.

Zidovudine (AZT) perinatal transmission prophylaxis regimen - ACTG 076 protocol:

  • Treatment during pregnancy: treatment with AZT should be initiated after the 14th week of pregnancy and continued until labor. Three 100 mg capsules (300 mg) every 12 hours should be used.
  • Treatment during labor: treatment should be started using a continuous IV infusion of AZT at an initial dose of 2 mg/kg diluted in 5% dextrose to be administered over one hour, followed by a maintenance dose of 1 mg/kg in a continuous infusion until delivery. IV AZT comes in 200-mg vials; therefore, 4-5 vials may be required.
  • Newborn treatment: treatment should be initiated within eight to 12 hours after birth. AZT syrup orally, 2 mg/kg, administered every six hours through the first six weeks. Alternatively, IV AZT at 1.5 mg/kg every six hours can be used in those who cannot tolerate oral treatment.

HIV-infected pregnant women without prior antiretroviral therapy:

  • HIV-positive pregnant women should be followed up for CD4+ count and viral load in the same way as any other adult.
  • They must be provided all the information available regarding the benefits and risks of antiretroviral therapy. Treatment should be offered after the 14th week of pregnancy.
  • If the status of the mother’s health requires she start combination antiretroviral therapy, this should be offered.
  • Zidovudine should be one of the drugs in any combination used. The whole treatment regime must be completed, including treatment during labor and neonate treatment.
  • For those whom antiretroviral treatment may be optional and/or who want to limit their exposure to these drugs, at least monotherapy with zidovudine should be offered. In these cases the risk of developing resistance to the drugs is counterbalanced by the resulting fall in the viral replication rate.

HIV-infected women already receiving antiretroviral therapy who become pregnant:

  • Patients found to be pregnant after the first trimester should continue their antiretroviral therapy. They should be provided with information about the benefits and risks involved.
  • If the patient is found to be pregnant before the 14th week, she should be informed of the potential teratogenic effects of the treatment  - which have yet to be confirmed.
  • If the patient decides to stop treatment, she should stop taking all antiretrovirals and restart treatment after the 14th week of pregnancy.

HIV-infected women in labor who have had no prior therapy:

  • AZT should be given to the neonate for the first six weeks after birth.
  • The status of the woman’s immune system and viral load should be determined postpartum in order to discuss initiating treatment.

Infants born to mothers who have received no antiretroviral therapy during pregnancy or labor:

  • Six weeks of AZT for the newborn child should be discussed with the mother and offered. Treatment should ideally start within 14 to 24 hours after birth.
  • Treatment initiated more than 14 days after birth is very unlikely to be successful.

Mode of Delivery

This should be determined based on the woman’s obstetric conditions and her viral load at the time of delivery. Various treatment regimes should be considered based on viral load results.

Emergency Caesarean Delivery: this is performed in response to an obstetric issue and has no protective effect. On the contrary, it increases the risk of vertical transmission (VT).

Elective Caesarean Delivery: this is performed without labor and with intact membranes. This should not be performed when the viral load is fewer than 1,000 copies, as it will have no beneficial effect on VT. When the viral load is higher than 1,000 copies, or unknown, an elective caesarean section should be scheduled for the 38th week of pregnancy. The risk of complications with this mode of delivery for HIV-negative women is at least twice as high as for normal delivery.

The final decision should be made based on the woman’s obstetric conditions, her health status and viral load, and the risks involved in conducting this procedure. Furthermore, an elective caesarean section should always be performed under appropriate sanitary conditions so as to significantly reduce the risks of maternal and perinatal morbidity and mortality. The availability of the necessary equipment and conditions should be checked before scheduling the delivery. Mothers treated with AZT to prevent VT should not continue taking this drug postpartum, and should be referred to their local HIV/AIDS specialists for attention and follow up. Mothers who were on antiretroviral therapy before pregnancy should continue treatment as per their doctor’s instructions.

Various studies are being conducted on the effects of vaginal washes on the prevention of the perinatal transmission of HIV. Cleansing the birth canal with Chlorhexidine at the time of delivery has shown good results in women with and without HIV.

A breast milk substitute should be recommended, avoiding breastfeeding as a possible source of VT.

FOLLOW-UP PROGRAM FOR CHILDREN OF HIV+ MOTHERS

Program Description
 
The program for prevention and control of VT  and its measures (breastfeeding stopped since 1986; delivery by caesarean section since 1989; and AZT prophylaxis since 1997 for all HIV+ pregnant women) are part of the National HIV/AIDS Prevention and Control Program.

In Figure 1, the total number of children born to HIV/AIDS seropositive mothers is shown from January 1, 1986 until October 25, 2005, coupled with prophylactic measures applied in the National HIV/AIDS Prevention and Control Program. Since 1986 there has been a national reference laboratory (LISIDA, according to the acronym in Spanish), just outside Havana, centralizing the following tests for all children of HIV/AIDS seropositive mothers: PCR (HIV polymerase chain reaction) on filter paper 15 days after birth - performed with phenylketonuria test. If PCR is negative, ELISA (enzyme-linked immunosorbent assay), WB (Western-blot), PCR, P-24 ag and ab (antigen and antibodies) tests are carried out at three, nine and 12 months of age.

Figure 1: Number of children born to HIV/AIDS seropositive mothers and prophylactic measures applied by the HIV/AIDS Prevention and Control Program, January 1, 1986 to October 25, 2005



Total number of births: 214
Source: Pedro Kourí Institute of Tropical Medicine

ELISA and WB tests are expected to be positive in a three-month old child, since maternal antibodies can pass through the placenta; but if PCR and P-24 ag are negative, this indicates that the virus did not pass the placental barrier, and the child is probably not infected. At nine months the tests are repeated, when it is frequently observed that the ELISA may be positive or weakly reactive and the WB undefined, because the child is eliminating the maternal antibodies that passed through the placenta. If PCR and P-24 ag are negative, this suggests that the child is not infected.

The ELISA and WB tests are repeated at 18 and 24 months of age to establish a definitive diagnosis. All WB bands should have disappeared and the ELISA should be negative. The child is considered healthy and discharged when two PCRs and two WBs show negative results. The child is then referred to their neighborhood family doctor for well-baby care, as is the case with other non-HIV infected children.

If the PCR performed 15 days after birth is positive, another PCR is rapidly carried out in whole blood. CD4 (T4 lymphocytes) and VL (viral load) are also determined to confirm  diagnosis and classify the child according to the 1994 classification by the CDC (Center for Disease Control and Prevention) in Atlanta, which includes children up to 13 years of age. HAART (highly active antiretroviral treatment) is begun, independent of clinical and immunological state, to avoid early viral replication and so that the child’s immune system may develop.

A child may be detected late and show a CD4 count lower than 15% in immunological studies and be clinically asymptomatic, but with a severe opportunistic infection indicating AIDS. The child is reclassified and HAART is started, sometimes even before the results of the new tests are received, since he/she is considered a clinical AIDS case, and the aim is to prevent greater immunological impairment.

All HIV/AIDS children are checked every three months to observe their growth and development; their immunological and nutritional states; and to give them a special diet for life, enriched in proteins, fats and carbohydrates. New options for case management are evaluated according to their development, treatment results and laboratory tests. The algorithm for the follow-up of these children is shown in Appendix 1.

REFERENCES

  1. Centers for Disease Control and Prevention. 1993 revised classification system for human immunodeficiency virus infection in children less than 13 years of age, MMWR 1994; 43(RR-12):1-15.
  2. González I, Dosal L, Díaz M, Pérez J. La transmisión materno-infantil del VIH/SIDA en Cuba. Rev Cubana Med Trop 2000;52(3):220-4.
  3. García L. Tratamiento de la infección VIH pediátrica: medidas generales. In: Español T, Ruiz I. Tercera Jornada tratamiento antirretroviral en pediatría. Barcelona: Springer-Verlag Ibérica; 2000:38-47.
  4. Peña JM. Transmisión vertical del VIH-1: hasta donde se puede reducir? Med Clin (Barc) 2000; 114:297-8.

THE AUTHORS

Ida González Núñez MD, PhD, is a 2nd Degree Specialist in Pediatrics, Full Professor and Junior Researcher.
Manuel Díaz Jidy MD, is a 2nd Degree Specialist in Internal Medicine and Junior Professor and Researcher.
Jorge Pérez Ávila MD, MS, is Professor and Researcher and Master in Clinical Pharmacology.
Hector L. Mengana Gutiérrez MD, is a 1st Degree Specialist in Obstetrics and Gynecology. 
Dr. Ida Gutiérrez MD, is a 1st Degree Specialist in Pediatrics.

All of the authors are associated with the Pedro Kourí Institute of Tropical Medicine, the national reference center for HIV/AIDS.

Appendix  1: Follow- up algorithm for children of HIV+ mothers.

 
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