Obstetrics and Gynecology

HIV and Pregnancy

HIV and Pregnancy

1. What every clinician should know

Clinical features and incidence

The human immunodeficiency virus (HIV) is a retrovirus that targets T helper lymphocytes and gains entry to these cells via the CD4 receptor. HIV causes disease by killing CD4+ T helper cells, which results in dysfunction of the host immune system. A healthy person has a CD4 cell count of 500-1,500 cells/uL. Acquired immunodeficiency syndrome (AIDS) is caused by HIV, and represents a later stage of the infection when the patient’s CD4 count falls below 200 cell/uL, making them susceptible to opportunistic infections and cancers as a result of the destruction of the immune system.

HIV transmission occurs when skin or mucosal barriers are broken in the case of sexual transmission, or when the HIV particle enters the blood directly via a blood transfusion or use of a contaminated needle. The natural history of HIV infection occurs in stages. Approximately 10 days after infection by the virus, patients experience the flu-like symptoms and lymphadenopathy that characterize acute infection and which can last from 2-4 weeks.

During acute infection, there is a high serum concentration of HIV viral particles (viral load). The risk of HIV transmission is highest at this stage of infection because of the high viral load. If tested for HIV antibody during this period, patients may test negative because the body has not yet mounted an antibody response. HIV antibody can be detected 3-12 weeks after infection but can take as long as six months in a minority of patients.

The next stage of HIV infection is the clinical latent period, which is of variable duration and, in the absence of antiretroviral medication, lasts an average of 8-10 years. During this period, the patient’s immune system is able to control the level of viral replication and the patient is asymptomatic. The third stage of HIV infection begins when the patient’s CD4 count is so depleted and the immune response so compromised that it can no longer control viral replication. The viral load rises and CD4 count falls, and finally patient enters the end stage of the infection when their CD4 count falls to less than 50 and they can die from opportunistic infections and cancers that result from immunosuppression.

The Center for Disease Control (CDC) estimates that by the end of 2009 there were 1,148,000 people living with HIV in the United States. In 2010, there were an estimated 47,000 new infections in the U.S., two thirds of which occurred among men who have sex with men. Among women, heterosexual contact is the leading cause of HIV acquisition, with a disproportionate number of new infections occurring in African American and Hispanic women living in the South.

Globally, HIV infection continues to be one of the leading causes of death among young adults living in sub-Saharan Africa. The primary mode of HIV transmission in high prevalence areas in sub-Saharan Africa is heterosexual contact, which results in HIV infection among millions of reproductive age women.

Obstetricians manage HIV infected patients in pregnancy, and should be familiar with general principals of the management of HIV infection antepartum, intrapartum and postpartum.

2. Diagnosis and differential diagnosis

Diagnostic criteria

HIV testing is recommended for all pregnant women in the first trimester, and again in the third trimester for patients in a high incidence area or with risk factors for HIV acquisition. This should be "opt out" testing, wherein women are informed that an HIV test will be sent with the routine prenatal tests unless they decline. The CDC recommends that there be NO requirement for written consent, as this has been shown to be a barrier to testing. However, individual hospitals may still require written consent for HIV testing.

HIV is diagnosed when the anti-HIV IgG antibody produced by human B cells is detected in human blood or saliva. However, during the ‘window’ period after infection and before mounting an antibody response, the diagnosis can be made in the absence of HIV antibodies if the HIV viral load is positive.

Screening asymptomatic patients for HIV is done with an enzyme linked immunoassay (EIA, sometimes called ELISA) test which evaluates for the presence of antibodies to the HIV virus. A positive EIA test is confirmed reflexively with a Western blot assay.

The HIV antibody test will be reported as positive, negative or indeterminate.

  • If reported as positive, this means that both the EIA and reflex western blot are positive and the patient is presumed to be HIV infected.

  • If reported as negative, this means that the EIA was negative, and the patient is either uninfected, or is in the ‘window period’ before an antibody response has been mounted. With newer third and fourth generation EIA assays, the period between infection and a positive EIA test is now as short as three weeks. In an asymptomatic patient with no recent flu like illness and no recent high risk behavior, a negative EIA can be interpreted as the absence of HIV infection.

  • If the test is reported as indeterminate, this means that the EIA was positive and the western blot detected antibodies to one of the HIV antigens (gp 120/160, gp 41, p24), but does not meet diagnostic criteria for a positive test. According to the CDC, a Western blot test should be interpreted as positive when it detects antibodies to gp 120/160 plus either gp 41 or p24.

Indeterminate tests may occur more frequently in pregnant women than the general population because of the presence of alloantibodies in pregnancy that can crossreact with the HIV test. Management of indeterminate testing can be challenging, as indeterminate results may occur in HIV uninfected individuals who have crossreacting antibodies OR in early infection when a patient is in the process of seroconverting.

In pregnancy, when antibody testing comes back as indeterminate, it is our practice to check a serum viral load to rule out acute infection. If the viral load is negative, we reassure patients that they are extremely unlikely to be HIV infected. We then repeat the test in 6-12 weeks.

Some labor and delivery units provide rapid HIV testing for women who have not had HIV testing during the pregnancy. Rapid tests can be performed on serum, whole blood or saliva and can yield results in 20-60 minutes. While test performance varies by the specific test being used, in general, the performance of rapid tests is comparable to that of the traditional antibody testing. However, rapid tests using oral fluid have slightly lower sensitivity (the ability of a test to detect disease) than rapid tests using blood. While results of rapid tests should be reported to the patient immediately, all rapid tests should have traditional confirmatory testing.

3. Management

The goal of management of HIV infection in pregnancy is to maintain maternal health through the pregnancy and to prevent perinatal transmission of HIV from the woman to her fetus. Without therapy, the risk of perinatal transmission is approximately 25%. The first large randomized controlled trial (RCT) of antiretroviral therapy for the prevention of perinatal transmission published in 1994 found that antenatal and intrapartum AZT therapy reduced the risk of perinatal transmission from 25% to 8%. Since that trial, multiple studies in the United States and abroad have shown that with antenatal combination therapy, intrapartum IV AZT, postpartum prophylaxis in the infant, and the avoidance of breastfeeding, perinatal transmission can be reduced to less than 1-2%.

Preconception

Women with HIV infection who are considering pregnancy should be counseled that the risk of perinatal HIV transmission to their child is lowest if their HIV is well controlled before the start of the pregnancy and remains well controlled during the pregnancy. Conception should be avoided if a patient has a low CD4 count. A patient’s health status should be optimized prior to conception by screening for and treating any sexually transmitted infections, anemia and latent TB infection. Medication regimens should be reviewed prior to attempting conception, and if a patient is taking efavirenz, they should be switched to another medication because of preclinical animal studies that showed an increased risk of neural tube defect associated with efavirenz. Other than this medication, in general, if a patient is stable on their antitretroviral therapy, they should continue their regimen while attempting conception.

Antepartum

One of the goals of HIV management during pregnancy is to suppress viral replication, thus decreasing viral load, and reducing the risk of perinatal transmission. Care should be coordinated with an HIV specialist if the obstetrician is not familiar with recommended medication regimens and the toxicities. Still, the obstetrician should be familiar with classes of medications, general toxicities and principles of therapy.

It has been estimated that if a patient is not treated with antiretroviral therapy, the majority of perinatal transmission occurs late in the antepartum period and in the intrapartum period. However, in studies that more closely examined transmissions that occurred in women with undetectable viral loads at delivery, early antepartum initiation of therapy was associated with lower risk of perinatal transmission than late antepartum initiation.

According the NIH guidelines, combination antiretroviral therapy (cART – which replaces the term highly active antiretroviral therapy or HAART), is recommended for all HIV infected pregnant women regardless of viral load. cART is defined as a combination of at least three antiretroviral medications from at least two antiretroviral drug classes. The rationale for antepartum treatment is that viral suppression is the strongest predictor of successful prevention of perinatal transmission, and cART is the most effective way to achieve viral suppression.

If a patient is stable on a cART regimen when she conceives, the recommendation is to continue therapy. Discontinuing therapy can result in viral replication and formation of resistance mutations in the virus. This risk is thought to outweigh any theoretical benefit of minimizing drug exposure to the fetus in the first trimester. However, if a patient is not yet on cART when they conceive and they are in good health, it is reasonable to delay initiation of therapy until after the first trimester. If a patient is immunocompromised and needs cART for her own health, initiation should not be delayed.

If a patient has hyperemesis that is not responsive to antiemetic therapy, cART can be stopped or initiation be delayed until after symptoms resolve, rather than allowing a patient to continue with suboptimal suppression.

A careful medication history should be taken, including all HIV medications taken, the side effects experienced with each medication and the results of any previous resistance testing. Baseline labs should include a T cell panel, viral load, and HIV genotype, which is the test to evaluate for the presence of resistance mutations. These may be present even in patients who have never taken medication because of transmission of resistant virus. A basic metabolic panel, complete blood count and hepatic function panel should also be checked prior to initiation of therapy to establish the patient’s baseline and to rule out underlying renal or hepatic disease that may affect the choice of medication.

In general, a cART regimen during pregnancy should contain two nucleoside reverse transcriptase inhibitors (NRTIs, “nukes”), and either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs, “non-nukes”). In addition to these three drug classes, there are integrase inhibitors and entry inhibitors, which are less commonly used in pregnancy. The NIH has published guidelines for the management of HIV in pregnancy and recommends the following as preferred and alternative cART regimens in pregnancy. Of note, medications with the most data about safety are designated as preferred.

NRTIs

1) Preferred

Zidovudine (AZT, Retrovir)

Lamivudine (3TC, Epivir)

2) Alternative

Tenofovir (TDF, Viread)

Emtricitabine (FTC, Emtriva)

Abacavir (ABC, Ziagen)

NNRTIs

1) Preferred

Nevirapine (NVP, Viramune)

2) Use in special circumstances

Efavirenz (ETR, Sustiva)

Protease inhibitors

1) Preferred

Atazanavir (ATV, Reyataz), given with ritonavir

Lopinivir + ritonavir (LPV/r, Kaletra, a fixed dose combination)

2) Alternative

Darunavir (DRV, Prezista), given with ritonavir

Saquinavir (SQV, Invirase), given with ritonavir

The most commonly used HIV medication regimen in pregnancy, and the one which has the most safety data, is Combivir plus Kaletra. Combivir is a fixed dose combination pill comprised of two NRTIs, AZT + 3TC. Kaletra is a PI, lopinivir, "boosted," as all PI’s are, with ritonavir.

An alternative starting regimen that uses the same drug classes as combivir and kaletra and which may be better tolerated is truvada (TDF + FTC) and atazanavir (ATV) boosted with ritonavir. All components of the truvada plus atazanavir regimen are dosed once daily. Of note because of the pharmacokinetics of PIs in pregnancy, most experts recommend increasing the dose of medications in this drug class in the second and third trimesters.

Caveats about specific medications

  • Abacavir (alternative NRTI) is associated with a hypersensitivity reaction and should only be used after testing for the HLA-B*5701 allele. Patients who test negative for this allele are not at risk for the hypersensitivity reaction and can take abacavir.

  • Nevirapine (preferred NNRTI) should not be used in women with CD4 counts over 250, as there is a risk of life-threatening lactic acidosis in immunocompetent patients who are treated with nevirapine.

  • Regimens that are given as one pill once per day include include Atripa and Complera. Atripla includes two NRTIs (TDF, FTC) and an NNRTI, efavirenz, which should not be given in the first trimester (see above). Complera is also two NRTIs (TDF, FTC) and an NNRTI, rilpivirine. The ease of dosing makes these regimens an attractive option for patients who have difficulty with taking multiple pills or remembering to take medication more than once a day. Because they are not first line regimens in pregnancy, consultation with an HIV specialist should be considered prior to initiation.

Side effects

Common side effects of antiretroviral medication include: headache, fatigue, nausea, vomiting, diarrhea. In addition to these, specific drug side effects include:

  • AZT - anemia

  • tenofovir - acute kidney injury

  • atazanavir - hyperbilirubinemia, usually asymptomatic.

Patients should be followed closely for evidence of medication toxicity and to ensure that viral suppression (defined as an HIV viral load below the limit of assay detection) is achieved. A basic metabolic panel, complete blood count, and hepatic function panel should be checked prior to initiation of therapy, one week after starting cART, and monthly thereafter. The patient should be followed with serum viral load measurements 2 weeks after starting therapy and every 4 weeks until reaching an undetectable viral load.

An adequate response to therapy is defined as a decrease of 1 log copy in the serum viral load in 4 weeks (example of 1 log copy decay is from 20,000 copies/mL to 2,000 copies/mL). Once an undetectable viral load has been achieved, testing frequency can decrease. We tend to continue to check viral load every 6-8 weeks. A viral load should be checked at 34-36 weeks to guide the decision about method of delivery. CD4 counts can be checked every 3 months.

All patients should be counseled about the importance of medication adherence, both for their own health, and to reduce the risk of transmission of HIV to their fetus. Poor adherence increases the risk of resistance mutations in the HIV virus, which may render one or more of their medications ineffective, and may mean the patient cannot be treated with any medication in that drug class moving forward. Poor adherence can also result in viral rebound, which increases the risk of perinatal HIV transmission.

In addition to the routine prenatal labs, which should include gonorrhea and chlamydia testing and a pap smear, an HIV infected patient should have the following labs sent:

  • Hepatitis B surface antibody titers to evaluate for immunity; if non-immune, the patient can be immunized during pregnancy.

  • Hepatitis C antibody.

  • CMV and Toxoplasmosis IgG and IgM when the patient’s CD4 count is less than 200.

  • All HIV infected patients should be screened for latent TB infection by PPD or quantiferon gold, and if screen positive, after active infection has been ruled out, should be treated with isoniazid daily or twice weekly for 9 months, starting after the first trimester.

  • Some providers check for antibodies to HSV-2 in all HIV infected patients and consider suppressive medication in the third trimester for those who test positive. The rationale for this approach is that even asymptomatic viral shedding increases the risk of HIV transmission. This approach has not entered official recommendations for the management of HIV in pregnancy.

An HIV infected pregnant patient with a low CD4 count should be treated with the same opportunistic infection prophylaxis as a non-pregnant patient:

  • Pneumocystis carinii (PCP) prophylaxis with TMP-SMZ (Bactrim) one double strength tablet daily when CD4 count is below 200

  • Toxoplasmosis prophylaxis is covered with the same medication used for PCP prophylaxis, TMP-SMZ 1 DS tablet daily, when CD4 count below 100

  • Mycobacterium avium complex (MAC) prophylaxis with azithromycin 1200mg orally weekly when the when CD4 count is below 50

Of note, CMV prophylaxis with ganciclovir 1gm orally three times daily has been shown to be effective in preventing disseminated CMV infection in patients who are CMV antibody positive and have CD4 below 50, but is not in official recommendations.

The following vaccines are recommended for HIV infected pregnant women:

  • Streptococcus pneumoniae, when the CD4 count is above 200.

  • Hepatitis B, in all susceptible patients by antibody titer.

  • Influenza virus, before and during influenza season.

  • Combined tetanus, diphtheria and pertussis vaccine (TDAP).

Invasive genetic testing should ideally be avoided in HIV infected pregnant women. The studies that show an increased risk of perinatal transmission with amniocentesis were done prior to the cART era. The largest study of women on effective ART regimens undergoing genetic amniocentesis included fewer than 160 patients and showed no transmissions. However, there remains a theoretical risk of transmission as a result of CVS and amniocentesis, and these procedures should be avoided when possible. If an HIV patient elects for an amniocentesis, it should be done after confirmation of adequate viral suppression and under ultrasound guidance with an effort to avoid the placenta.

Intrapartum

The goal of intrapartum therapy is to provide the infant with preexposure prophylaxis (PrEP) against HIV by achieving a high maternal serum medication level, which, through transplacental drug passage, results in fetal drug exposure before the infant is exposed to maternal blood at the time of delivery.

In general, the recommendation is to treat with IV AZT intrapartum with an initial loading dose of 2 mg/kg IV over 1 hour, followed by continuous infusion of 1 mg/kg/hour until delivery. For optimal maternal serum levels, this should be started 3 hours prior to delivery. If an urgent cesarean delivery (CD) is required for obstetric reasons, an effort should be made to give the loading dose prior to delivery.

The most recent NIH treatment guidelines state that women with an undetectable viral load prior to delivery do not require intrapartum IV AZT, based on results of a study that found that the risk of perinatal HIV transmission was below 1% in women with an undetectable viral load among women both with and without intrapartum AZT.

Method of delivery

There are multiple studies addressing the question of whether a cesarean delivery reduces the risk of perinatal HIV transmission. It is generally agreed upon that a cesarean delivery reduces the risk of perinatal HIV transmission in women with viral loads greater than 1000 copies/mL. The NIH guidelines recommend that women deliver by planned cesarean delivery at 38 weeks when their serum viral load is greater than 1000 copies/mL. The gestation was chosen order to reduce the risk of a patient presenting in active labor or after membrane rupture.

When patients who are known to be viremic present in active labor or after rupture of membranes, they should be counseled that the role of CD to reduce the risk of perinatal HIV infection in this situation is unclear, and the decision should be made on an individual basis depending on the patient’s viral load, immune status, stage of labor, and duration since membrane rupture.

In women who labor, an effort should be made to avoid artificial rupture of membranes, the use of fetal scalp electrodes, operative vaginal delivery, and episiotomy because of the potential risk of transmission as a result of introduction of maternal blood or vaginal secretions into fetal tissue or circulation.

Labor augmentation with oxytocin should be used to expedite delivery when it is not progressing normally. If there is a postpartum hemorrhage, use of methergine should be avoided in women taking PIs, as the combination can result in excessive vasoconstriction. Alternative uterotonics should be used as a first line.

Postpartum

Planning for the postpartum transition to an HIV care provider should begin prior to delivery to ensure a smooth transition. U.S. guidelines currently recommend cART for all HIV infected individuals with a CD4 count below 500 and women who meet this criterion should continue their medication postpartum. Patients should have early postpartum follow up, as they are at risk for reduced medication adherence in the postpartum period with the altered sleep schedule, mood changes, and the fact that perinatal transmission is no longer a concern.

Women with a CD4 count greater than 500 should be counseled about the risks and benefits of continuing therapy after pregnancy. There is a trend toward earlier treatment as emerging research suggests that early treatment may slow disease progression. The balance is being tipped in the direction of continuing treatment after pregnancy as drug regimens become simpler and more tolerable. Ideally, this decision should be made in conjunction with the provider who will be caring for the patient long term.

In women who choose to stop cART after pregnancy, regimens that include NNRTIs require a "tail" of NRTI continuation to reduce the risk of development of resistance mutations. This is because of the long half-life of NNRTIs; when all three medications are stopped at the same time, the NNRTI component is unopposed in maternal serum and in some cases results in resistance. The tail refers to the continuation of the two NRTIs for 7-30 days after discontinuing the NNRTIs.

Infant prophylaxis is a critical component of prevention of perinatal transmission strategies. All infants born to HIV infected women should be treated with AZT prophylaxis starting immediately after delivery to 6 weeks of life. Infants born to women who were viremic at delivery and had a vaginal delivery, or who did not receive antepartum or intrapartum therapy, or have a known resistant virus, may benefit from the addition of another medication to the AZT. Current guidelines recommend three doses of nevirapine in addition to the 6 weeks of AZT.

All infants born to HIV infected women should have an HIV DNA test sent at the time of delivery. If this test is positive, it suggests antepartum HIV transmission. If testing is negative at birth and positive at 6 weeks of life, this is consistent with intrapartum transmission. Antibody testing should not be performed in neonates as maternal HIV antibody crosses the placenta and may result in a false positive antibody test in the baby.

Patients should be advised to feed their infants with formula rather than breast milk, since the HIV virus is present in breast milk and can result in transmission of HIV from a woman to her child.

4. Complications

It can be helpful to think of complications of HIV infection in pregnancy in two categories: the effect of pregnancy on HIV, the effect of HIV on pregnancy.

Effect of pregnancy on HIV infection

Multiple studies have sought to evaluate whether pregnancy results in more rapid progression to AIDS. Reviews summarizing the data conclude that pregnancy does not accelerate HIV disease progression. The fact that HIV infected women who become pregnant are exposed to cART and then interrupt therapy also does not appear to increase the rate of disease progression.

Effect of HIV infection on pregnancy

It can be difficult to determine whether adverse outcomes seen among HIV infected women are a result of the underlying disease or the medications used to treat the disease. Some studies have shown that HIV infected women taking ART have a small increased risk of preterm birth while others have failed to find an association. Similarly, some studies have shown that PI therapy is associated with an increased risk of glucose intolerance, whereas others have not. In both cases, providers should be aware of these potential risks but should not withhold therapy, as the benefits of antiretroviral therapy in pregnancy outweighs these risks.

5. Prognosis and outcome

The management of HIV has made tremendous progress since the early days of HIV therapy. More effective and less toxic therapy has improved outcomes of HIV infected pregnant women and their children. With appropriate treatment, the risk of perinatal transmission can be reduced to less than 1-2%. Because a diagnosis of HIV is no longer a death sentence, with appropriate therapy, most women can expect to live to see their children reach adulthood.

6. What is the evidence for specific management and treatment recommendations

http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.

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Townsend, CL, Cortina-Borja, M, Peckham, CS, de Ruiter, A, Lyall, H. "Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006". AIDS. vol. 22. 2008. pp. 973-81.

Tubiana, R, Le Chenadec, J, Rouzioux, C. "Factors associated with mother-to-child transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-control study nested in the French perinatal cohort (EPF-ANRS CO1)". Clin Infect Dis. vol. 50. 2010. pp. 585-96.

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