HIV in Pregnancy: A Comprehensive Review
Dr. Howard L. Minkoff
Chairman, Department of Obstetrics and Gynecology
Maimonides Medical Center, Brooklyn, New York,
Distinguished Professor of Obstetrics and Gynecology
SUNY-Health Science Center,Brooklyn, NY (USA)
The transformation of the human immunodeficiency virus (HIV) epidemic over the last 20 years has been remarkable. With access to appropriate therapies, clinicians can now offer infected women a much improved prognosis as well as a very high likelihood of birthing children who will be HIV uninfected. Prevention of transmission of HIV from mother to fetus or newborn (vertical transmission) is a major goal in the care of pregnant women infected with HIV. In caring for HIV-infected pregnant women and prescribing the antiviral medications, obstetricians must always bear in mind their dual responsibilities, providing optimal care to the mother and reducing the likelihood of mother-to-child transmission of HIV. To accomplish these goals, the physician must first monitor the patient's immunological and virological status including resistance testing. The results of these tests will guide the clinician in choosing when to initiate therapy and in deciding whether to use regimens directed solely at transmission interruption or those that will simultaneously treat the mother's infection.
When using highly active antiretroviral therapy, physicians must be cognizant of the pregnancy-specific risks associated with some of the component agents. The core goal of all medical therapy is to bring the patient's viral load to an undetectable level. When that goal is reached, the chance of transmission to the child is minimized, the need for a cesarean delivery is reduced, and the patient's prognosis is optimized. None of the advantages cited above can be achieved unless all women have their HIV status determined as early in pregnancy as possible.
In this article, the most recent developments in the field are summarized in a fashion that should allow the integration into the practice of obstetrics and thereby assure the HIV-infected women the best possible prognosis for themselves and for their children. The focus of this work is on the dual responsibilities of obstetricians, assuring the health of women and minimizing the risks of transmission.
It is the responsibility of all clinicians taking care of pregnant women to be certain that serostatus is determined as early in pregnancy as possible. The Institute of Medicine recommends an informed right of refusal approach to testing. Although such an approach would require that a prenatal patient be informed that she was going to be tested for the virus that causes AIDS and that she had the right to refuse such a test, a written affirmative consent would not be required. Despite the increasingly simple and straightforward approach recommended for prenatal testing, because approximately 15% of HIV infected women receive no or minimal care and 20% do not initiate care until the third trimester, a number of women still arrive in labor and delivery suites with unknown serostatus. There are compelling data to suggest that intrapartum and early neonatal prophylaxis, even in the absence of antepartum therapy can reduce the risk of mother-to-child transmission.
Therefore, efforts should be made during labor to rapidly discern the serostatus of those women whose results were not previously known. Although the current generation of rapid tests (often using a single enzyme-linked immunosorbent assay) are not as reliable as the standard approach used for prenatal testing (one or two enzyme linked immunosorbent assays followed by a confirmatory Western blot), they are still sufficiently sensitive to identify women who should be offered therapy while confirmatory tests are pending. Patients should be informed that if the confirmatory tests turn out to be negative (which they often will in low-prevalence communities), then treatment of the infant would be discontinued.
Treatment of HIV Infection in Pregnant Women:
Since the advent of highly active antiretroviral therapy in 1996, though associated with serious side effects, they have been shown to be very effective at keeping viral replication in check and to dramatically improve the prognosis and health of HIV infected individuals. Thus, the first responsibility of obstetricians is to assure that these medications are used appropriately in the setting of pregnancy. The key points for the therapy are:
- Monitor women to know when highly active antiretroviral therapy should be instituted or altered.
- Know the appropriate therapies to use in the setting of pregnancy.
Monitoring Virological and Immunological Status:
Studies of the natural history of HIV infection have elegantly defined the relationship between shifts in viral load, progressive immunological deterioration, and subsequent clinical decline. More recent data have highlighted both the difficulty of sustaining long-term adherence to highly active antiretroviral therapy, and the fact that no obvious clinical disadvantage had been associated with therapy that is initiated a bit farther into the course of the disease.
The cornerstones of monitoring remain viral loads and CD4 counts. In the nonpregnant HIV infected individual, treatment initiation is now recommended when the CD4 count falls below 350 mm3 or when plasma HIV ribonucleic acid (RNA) levels exceed 30,000 copies/mL (b-deoxyribonucleic acid assay) or 55,000 copies/mL (reverse transcription polymerase chain reaction assay). Counseling regarding implementation of these guidelines must be individualized and, in addition to a discussion of immune and virological status, should include factors such as a woman's willingness and readiness to undertake a lifelong commitment to therapy; the potential benefits and risks of initiating therapy in asymptomatic individuals; and the likelihood, after counseling and education, of adherence to the prescribed treatment.
Once a decision to begin therapy has been made, viral load monitoring provides a gauge of the success of the intervention. In pregnancy, that monitoring should occur monthly until the viral load is undetectable and then be obtained every 2-3 months. With appropriate therapy, viral load should be seen to drop by over one log within the first month of therapy and should eventually become undetectable. The speed with which that occurs will vary with the baseline load. The higher the load, the longer the time till undetectable levels are reached; however, in all circumstances, that goal should be achieved within 6 months. If that goal is not reached, or if after it is attained, subsequent tests reveal a reemergence of detectable levels of virus beyond a transient low-level viremia, then therapy must be deemed a failure and a decision as to a new therapy will have to be made.
Most recently, resistance tests have become a standard component of HIV care. Currently, two types of testing are available, phenotypic and genotypic, each with distinct advantages and disadvantages. Phenotypic testing is a measure of the activity of the virus under set conditions, whereas genotyping is a measure of structure.
- Phenotypic Testing: it compares the ability of the virus to replicate in various concentrations of an antiretroviral drug with its ability to replicate in the absence of the drug. As such, they are somewhat analogous to bacterial sensitivity tests with which most physicians are familiar. Results are usually expressed as the amount of drug required to inhibit viral production in vitro by 50% although other levels such as 90% or 95% inhibition can be used. In general, if the amount of drug required to inhibit viral production by 50% is four-fold or greater for the patient's virus than the control strain, then the patient's strain is considered resistant.
- Genotypic Testing: it seeks to detect mutations in the genes that control replication of the virus. These mutations result in the substitution of amino acids in the proteins produced. The significance of these point mutations is determined by correlating specific mutations with phenotypic resistance as measured by viral susceptibility assays and correlation with clinical response to therapy. Mutations can have adverse consequences in several ways. Primary mutations affect the binding of the drug to its target site, thus increasing the amount of drug necessary to inhibit the enzyme activity. However, the resultant mutant strain of the virus may be less able to replicate in the host and to induce immunological compromise. Other, secondary mutations make that relatively less "fit" mutant virus more pathogenic. Thus, those secondary changes work by improving the ability of the virus with primary mutations to replicate and cause immunological damage (i.e. they restore fitness). The number of mutations required to cause a clinically relevant effect varies with the agent in question. Thus, the rate at which resistance develops will depend on the number of mutations necessary to create a significant change in susceptibility.
Certain limitations are present for both genotypic and phenotypic assays. Both types of assays require a plasma HIV RNA level above 1,000 copies/mL. In addition, the assays may not detect resistant species that constitute 20% or less of the population of circulating viruses. Resistance testing is more useful for ruling out, than for ruling in, therapies to be used in a given patient. That is because the absence of resistance may merely reflect the reemergence of that wild type strain and the inability, in that circumstance, for the assays to detect the minority mutant strain. Currently, genotypic assays are more widely available commercially than phenotypic assays. Cross-resistance to other drugs within a class such as protease inhibitors can be difficult to predict based only on genotype.
There are several defined circumstances in which clinicians should use these tests. The most common indication for testing is treatment failure. Treatment failure is defined as the failure to attain an undetectable level of virus or the persistent presence of virus after it had become detectable. If it has been determined that failure has occurred, resistance testing should be performed before the failing regimen is discontinued. This is to prevent the overgrowth of wild type strain that might occur after the regimen is discontinued, such that resistant strains would not be detected even though they would be "lying in wait" for the reinstitution of some components of the regimen. Resistance testing can also be helpful in the setting of an individual who has recently seroconverted. It has also been suggested that all HIV-infected pregnant women will benefit from resistance testing, but a few caveats are necessary in that regard. The goal in pregnancy is always to maintain a viral load under 1,000 because that would both allow consideration of a vaginal delivery and would minimize the mother-to-child transmission rate. If a regimen were successful in dropping the load to or below that level, it would be impossible to perform resistance testing in any case. If the regimen is unsuccessful, then resistance testing is warranted regardless of the patient's pregnancy status.
Drug Therapy for Maternal HIV Disease in Pregnancy:
In pregnancy, the threshold for starting therapy is somewhat lower. Mother-to-child transmission rates are linked to viral loads, and rates start to climb well before viral loads of 55,000 copies are reached. Cesarean deliveries are recommended for women whose viral loads exceed 1,000 copies. When initiating treatment, the clinician must bear in mind that choosing an appropriate second-line regimen is even more difficult than choosing an initial course of therapy. That fact should reinforce two rules regarding the initial decision to commence antiviral therapy of HIV-infected women.
- Adherence to therapy is crucial
- The choice of a first-line course of therapy should always include a consideration of the possible need to deal with the failure of that regimen.
Haphazard or intermittent compliance with a drug regimen is a formula for the development of resistant virus. Even very brief drug discontinuation has been associated with the replacement of wild strain virus with mutant strains that are resistant to therapeutic agents. Therefore, it is critical that time and effort is expended by providers to educate patients about the need to start treatment only after they are able to commit to rigorous and lifelong adherence to complex regimens. Additionally, providers must assist patients in developing the tools that will aid them in maintaining successful regimens.
It is useful to choose a regimen that "spares" one class of antiviral agent. Thus, a regimen should spare protease inhibitors or non-nucleoside reverse transcriptase inhibitors or both. In fact, there are increasingly popular regimens that employ three nucleoside reverse transcriptase inhibitors alone. When those regimens are used, the patient is assured that if resistance develops, there are classes of drugs available to which the virus has not yet been exposed and to which they are unlikely to have resistance. A critical factor to recognize is that there are often poor results with antiretroviral regimens instituted in the wake of virological failure with a previous regimen.
Preclinical and Clinical Data Relevant to the Use of Antiretrovirals in Pregnancy:
Source: US Public Health Service Task Force. Perinatal HIV guidelines Working Group Members.
|Antiretroviral Drug||*FDA Pregnancy Category||Placental Passage (newborn:mother drug ratio)||Long-term animal Carcinogenic Studies||Animal teratogen Studies|
|I. Nucleoside and nucleotide analogue reverse transcriptase inhibitor|
|Zidovudine (Retrovir, AZT, ZDV)||C||Yes||Positive (non-invasive epithelial tumors)||Positive (rodent, near-lethal dose)|
|Zalcitabine (HIVID, ddC)||C||Yes||Positive (rodent, thymic lymphomas)||Positive (rodent, hydrocephalus)|
|Didanosine (Videx, ddI)||B||Yes||Negative||Negative|
|Stavudine (Zerit, d4T)||C||Yes||Not Completed||Negative (but sternal bone calcium decreases in rodents)|
|Lamivudine (Epivir, 3TC)||C||Yes||Negative||Negative|
|Abacavir (Ziagen, ABC)||C||Yes||Not Completed||Positive (rodent, skeletal malformations)|
|Tenofovir DF (Viread)||B||Yes||Not Completed||Negative (osteomalacia in juvenile animals)|
|II. Non-nucleoside reverse transcriptase inhibitors|
|Nevirapine (Viramune)||C||Yes||Not completed||Negative|
|Delavirdine (Rescriptor)||C||Unknown||Not Completed||Positive (rodent, ventricular septal defect)|
|Efavirenz (Sustiva)||C||Yes||Not completed||Positive (monkey, anencephaly, microphalmia)|
|III. Protease Inhibitors|
|Indinavir (Crixivan)||C||Yes||Not Completed||Negative (but extra rib in rodents)|
|Ritonavir (Norvir)||B||Yes||Positive (rodent, liver adenomas & carcinomas)||Negative (but cryptorchidism in rodents)|
|Saquinavir (Fortovase)||B||Minimal||Not Completed||Negative|
|Nelfinavir (Viracept)||B||Unknown||Not Completed||Negative|
|Amprenavir (Agenerase)||C||Unknown||Not Completed||Negative (but deficient ossification and thymic elongation in rodents)|
|Lopinavir/Ritonavir (Kaletra)||C||Unknown||Not Completed||Negative (but delayed skeletal ossification)|
|* FDA pregnancy categories, please go to Drugs In Pregnancy.|
Pregnancy Consideration With Highly Active Antiretroviral Therapy Regimens:
Although recommendations regarding antiviral therapy should not be modified because of pregnancy, a few comments are deserving of note.
- Zidovudine, the first agent clearly linked to significant reductions in rates of mother-to-child transmission of HIV, should be used whenever possible as a component of highly active antiretroviral therapy regimens. The current standard zidovudine dosing regimen for adults is 200 mg three times daily or 300 mg twice daily.
- The potential perinatal risks of agents must be considered when choosing a highly active antiretroviral therapy regimen. Nucleoside reverse transcriptase inhibitors were the first class of drug used for treatment of HIV, and there is a greater experience with their use than with other classes of drug, the vast majority of which is reassuring. These agents have been generally well tolerated and have not been demonstrated to be teratogenic in humans. However, concerns have been raised about potential adverse effects on both mothers and infants related to the avidity of these drugs for mitochondria. In the mother, clinical disorders associated with mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy, pancreatitis, hepatic steatosis, and lactic acidosis.
Although these serious morbidities appear to be rare, providers caring for HIV-infected women receiving nucleoside reverse transcriptase inhibitor analogue agents should be aware of the risk and monitor accordingly. One approach would be to monitor hepatic enzyme levels during the last trimester and to aggressively investigate all new symptoms. Concerns about mitochondrial toxicity have also been raised with regard to neonates. Other concerns that have been raised with regard to nucleoside reverse transcriptase inhibitors have included preterm births, mutagenesis, and febrile seizures. Among the non-nucleoside reverse transcriptase inhibitors, efavirenz should not be used in the first trimester because of reported teratogenic effects in monkey models.
Despite these concerns, pregnant women in the United States tend to receive highly active antiretroviral therapy as often as other women with similar immunological status. All pregnant women on antiretroviral therapy should have regular monitoring of liver functions and blood counts to detect toxicity as early as possible.
Prevention of Transmission of HIV:
In the absence of interventions, the reported frequency of mother-to-child transmission varies widely across the globe with rates ranging from 10% to 60%. The range reflects differences in patterns of breast-feeding, viral loads, and obstetric practices. In United States, as many as 2000 children each year were infected through birth. However, by the year 2000, only 174 pediatric AIDS were reported. That remarkable decline reflects the development of interventions that were built upon research detailing the timing and determinants of transmission. It is estimated that 70% of mother-to-child transmission occur at delivery, and about 30% of transmissions occur in utero. The factor that best predicts the likelihood of infection in the neonate is maternal viral load, and those on antiretroviral therapy still have lower rates of transmission.
Factors other than viral load have been linked to mother-to-child transmission include prolonged rupture of membranes, vaginal delivery, prematurity, drug use, and perhaps most importantly from the international perspective, breast-feeding. In fact, in many parts of the world, it is estimated that breast-feeding can account for up to 50% of transmission. Although clinicians will undoubtedly continue to confront nettlesome clinical scenarios for which only general guidelines can be offered. Some recommendations based on evidence-based studies are:
- All pregnant women should have prenatal HIV tests administered per the recommendations of the Institute of Medicine (i.e., routinely with an informed right of refusal).
- Testing should be performed in the intrapartum and/or neonatal periods if serostatus has not been previously determined.
- All HIV-infected women should be monitored with (i) viral loads every month until the virus is undetectable and then every 2-3 months, (ii) CD4 counts - absolute number or percent - each trimester, and (iii) resistance testing if they have recently seroconverted or if they have failed therapy.
- Pregnant women should have access to all of the same therapies as non-pregnant women with the following exceptions: susteva, hydroxyurea, and stavudine and didanosine in combination should not be used unless other regimens are not available.
- The goal in pregnancy should be to bring the viral load to levels that are undetectable.
- All pregnant women should receive antiretroviral therapy. In the vast majority of circumstances that therapy should be highly active regimen that includes zidovudine. If a woman has a low viral load that would not require therapy if she were not pregnant (eg, less than 1,000 copies), then use of mono-therapy can be considered with the understanding that there may be a small risk of the development of resistance.
- Women identified as HIV infected in labor should be treated with either: (i) zidovudine in labor and 6 weeks to the neonate, (ii) nevirapine, a single dose to the mother in labor and a single dose to the neonate, (iii) zidovudine-lamivudine in labor and to the neonate for 1 week, or (iv) both nevirapine as above and the zidovudine regimen as above.
- Cesarean delivery should be recommended to all women with a viral load greater than 1,000 copies.
- Discontinuation of highly active antiretroviral therapy in the postpartum period is appropriate in those circumstances in which it would not have been used in the first instance if the woman had not been pregnant.
The American College of Obstetricians and Gynecologists (ACOG) generally recommends that scheduled cesarean deliveries not be performed before 39 weeks of gestation. In women with HIV infection, however, delivery at 38 completed weeks of gestation is recommended to reduce the likelihood of onset of labor or rupture of membranes. Amniocentesis to determine fetal lung maturity in pregnant women infected with HIV should be avoided whenever possible. Because morbidity is increased in HIV-infected women undergoing cesarean delivery, physicians should consider using prophylactic antibiotics during cesarean delivery. The risks from cesarean section, which are greater for the mother, must be balanced with the benefits expected for the neonate. The patient's autonomy must be respected when making the decision to perform a cesarean delivery, because the potential for maternal morbidity is significant.
Prevention of transmission of the human immunodeficiency virus (HIV) from mother-to-child is major goal in the care of pregnant women infected with HIV. Preoperative maternal health status affects the degree of risk of maternal morbidity associated with cesarean delivery. All women should be clearly informed of the risks associated with cesarean delivery. Ultimately, the decision to perform a cesarean delivery must be individualized in each case according to circumstances. HIV disease is still an illness that demands the best physicians have to offer as scientists, clinicians and human beings.
- Institute of Medicine National Research Council. Reducing the odds: Preventing perinatal transmission of HIV in the United States. Washington: National Academy Press, 1999.
- The European Collaborative Study and the Swiss Mother+Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000;14:2913-20.
- Centers of Disease Control and Prevention. Administration of zidovudine during late pregnancy and delivery to prevent perinatal HIV transmission - Thailand 1996-1998. MMWR Morb Mortl Wkly Rep 1998;48:151-4
- American College of Obstetricians and Gynecologists. Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. ACOG committee opinion no. 219. Washington: American College of Obstetricians and Gynecologists, 1999.
- The Perinatal Safety Review Working Group. Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: Absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000; 25:261-8.
- Minkoff HL. Human Immunodeficiency Virus Infection In Pregnancy. Obstetrics & Gynecology Vol.101, No. 4, April 2003, 797-810.
Gratitude is expressed to Dr. Howard L. Minkoff for sharing is work and research with us. His support and encouragement is priceless to this project and millions of women around the world will be benefited with his expertise in this area. The guidelines are general and intended to be adapted to many different situations, taking into account the needs and resources particular to the locality, the institution, or the type of practice. Variations and innovations that improve the quality of patient care are to be encouraged rather than restricted. The purpose of these guidelines will be well served if they provide a firm basis on which local norms may be built.
The readers are encouraged to visit the web site of the Centers of Disease Control and Prevention for up to date information on HIV research and treatment:
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