The guiding principle in the care of HIV-infected pregnant women continues to be strict adherence to the standards of care that apply to all other HIV-infected individuals. The first step in that care is the monitoring of immune status with CD4 counts and viral loads. Checking for viral resistance also has become a key component of monitoring regimens (vide infra). Viral loads can be checked every 3 to 4 months. Once a decision is made to initiate therapy, viral-load monitoring should occur monthly until virus is no longer detectable and then can be cut back to three or four times per year. With appropriate therapy, a drop of 1.5 to 2 logs within 1 month of initiation of treatment can be anticipated. The recommended timing of initiation of therapy (vis-a-vis CD4 counts and viral loads) has undergone several revisions over the last few years. This evolution reflects the awareness that despite the clear benefits of therapy, there also are well-recognized toxicities that make it difficult to maintain strict adherence. Some data suggest that no harm befalls patients who delay therapy until viral loads rise and CD4 counts drop further than had previously been recommended. Current guidelines are to start therapy in nonpregnant women when the viral load is >100,000 copies or when the CD4 count drops below 350 cells/mm³. In the nonpregnant state, when those thresholds are passed, HAART should be initiated. The appropriate guidelines for initiating therapy in pregnancy follow.

Resistance testing has become a staple of care for HIV-infected individuals. The viral RNA is reverse transcribed
into complementary DNA (cDNA) by the viral reverse transcriptase through use of a cellular lysine tRNA molecule as a primer; subsequently, the RNAase activity of the reverse transcriptase degrades the viral RNA template. The reverse transcriptase incorporates an incorrect nucleotide every 1,500 to 4,000 bases, which explains the rapid occurrence of mutations. Some of the resulting mutations provide a survival advantage, leading to drug-resistant strains.

There is accumulating evidence that transmitted resistant mutants may persist for indefinite periods after initial infection, these viral variants may be detectable by standard assays used in clinical practice, the prevalence of resistance in antiretroviral-naive patients is increasing, and baseline resistance may be associated with adverse virologic outcomes. For these reasons, baseline HIV resistance testing is now recommended for all patients with established infection, including pregnant women, prior to initiating treatment.

Most randomized trials of resistance testing have demonstrated that those assigned to study arms with access to resistance test results have a greater reduction in viral load after the initiation of salvage therapy, though follow-up generally has been short. These tests are recommended for individuals prior to commencing therapy or after failed therapy. Treatment failure is defined as the failure to attain an undetectable level of virus or the persistent presence of virus after it has become undetectable. Transient low-level viremia may not be the same as a drug failure, and sustained response to treatment can occur even in the setting of occasional low-level viremia. Blood for testing should be obtained before a failing regimen is discontinued lest wild-type virus overgrow before the test is performed. In that circumstance, an individual with no apparent resistance would still fail therapy when reexposed to drugs that favor the growth of the resistant virus over the wild-type strain. In essence, resistance testing is more useful for ruling out, than for ruling in, therapies to be utilized in a given patient. That is because, as noted, the absence of resistance may merely reflect the reemergence of a wild-type strain after an antiretroviral agent has been withdrawn. In that circumstance, the assays will not detect a low volume of a minority mutant strain. However, if the patient is reexposed to the offending agent, the resistant strain may again attain dominance. It is not possible to perform resistance studies if there are <1,000 copies of detectable virus.

Currently, two types of testing are available—genotypic and phenotypic—each with distinct advantages and disadvantages. Phenotypic testing compares the ability of the virus to replicate in various concentrations of an antiretroviral drug, with its replication in the absence of the drug. In general, if the amount of drug required to inhibit viral production by 50% is fourfold or greater for the patient virus than the control strain, then the patient’s strain is considered resistant. Specific cutoffs for resistance for each drug are based on clinical correlation, and the serum levels usually are attainable for a given drug. Measurement of drug levels per se has not yet been shown to be useful addendums to standard monitoring.

Genotypic testing is directed at detecting mutations in the genes that encode reverse transcriptase and protease formation by the virus. Point mutations in the virus result in the substitution of amino acids in the proteins produced (i.e., reverse transcriptase or protease). The significance of these point mutations has to be determined by correlating specific mutations with phenotypic resistance as measured by viral susceptibility assays and correlation with clinical response to therapy. Genotypic changes leading to resistance are believed to result from the combination of the rapid turnover of HIV (10⁷ to 10⁸ rounds of replication per day) and the high error rate of reverse transcriptase when replicating the nearly 10,000 nucleotides present in the HIV genome. Genetic mutants with resistance to antiretroviral agents are then selected by evolutionary pressure when incompletely suppressive drug regimens are used. The rate at which resistance develops will depend on the number of mutations necessary for a significant change in susceptibility to occur. The genetic basis for resistance must be understood before the impact of a specific mutation can be predicted. In addition, mutational interactions may make prediction of phenotype (i.e., susceptibility) difficult when multiple mutations are present. Prediction of cross resistance to other drugs within a class such as protease inhibitors (PIs) can be difficult to predict based only on genotype. In clinical practice, most clinicians will rely on algorithms developed by panels of experts or to online databases. Obstetricians should interpret and act on these results in consultation with an expert in the field.

During pregnancy, HIV drug-resistance testing is recommended for several subsets of women. All pregnant women who are not currently receiving antiretroviral therapy should be tested before starting treatment or prophylaxis. Additionally, all pregnant women who are receiving antenatal antiretroviral therapy and have virologic failure with persistently detectable HIV RNA levels or who have suboptimal viral suppression after initiation of antiretroviral therapy should undergo resistance testing. While it would be ideal to have results back before starting therapy in pregnancy, it has been recommended that in certain circumstances (e.g., late registrant), empiric initiation of antiretroviral therapy before results of resistance testing are available may be warranted, with adjustment as needed once the results are known. Ideally, the development of resistance would be avoided in the first instance. Several steps can be taken toward that end. The use of highly active antiretroviral combination therapy to maximally suppress viral replication during pregnancy is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Finally, all pregnant women should be counseled about the importance of adherence to prescribed antiretroviral medications to reduce the potential for development of resistance.

Although perinatal transmission of resistant virus has been reported, it appears to be unusual, and there is little evidence that the presence of resistance mutations increases the risk of transmission when current recommendations for antiretroviral management in pregnancy are followed. In studies in which transmitting mothers had mixed viral populations of wild type and virus with low-level zidovudine (ZDV) resistance, only wild-type virus was found in the infants, and other studies have suggested that drug-resistance mutations may diminish the fitness of the virus, possibly leading to a decrease in transmissibility. Neither resistance to NVP that develops as a result of exposure to single-dose NVP nor exposure to single-dose NVP in a prior pregnancy have been shown to affect perinatal transmission rates.

The standard approach to the medical treatment of HIV infection continues to evolve at a rapid pace (Table 20.1). An example of the rate of change in recommended treatments is the pace of new guidelines by the International AIDS Society–USA panel; they have been revised seven times since 1996. However, while the number of HAART regimens that have been shown to achieve persistently low viral loads continue to increase, they still fall into one of a few broad categories. The original regimens described in 1996 included dual nucleoside therapy accompanied by a PI; now, the nucleoside “backbone” may be supplemented by a non-nucleoside, a “boosted” protease, or a third nucleoside. Currently, there are numerous nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and PIs approved for therapy, with many others in the pharmaceutical “pipeline.” So, theoretically, a large number of choices within these categories exist. However, certain medications should not be used in combination. For example, ZDV and stavudine (d4T) have overlapping toxicities. Didanosine (ddI) and zalcitabine (ddC) should not be used in combination, and ddI and d4T have been linked to several fatal cases of mitochondrial toxicity in pregnancy.

The clinician who is preparing to care for an HIV-infected individual must consider the following: when to start therapy, which therapy should be used, and when the regimen should be altered. The trigger for starting antiretroviral therapy in nonpregnant women is either symptomatic HIV disease or, for patients without symptoms, after the CD4 count declines below 350 cells/mm³ but before it reaches 200 cells/mm³ (Table 20.2). Individualization continues to guide the timing of treatment initiation, with consideration of patient readiness, rate of CD4 cell count decline, and plasma HIV-1 RNA level. Thus, with a count between 200 cells/mm³ and 350 cells/mm³, a provider might be more aggressive in promoting the initiation of therapy if the count is dropping rapidly or the viral load is >100,000 copies. In the near future, it can be anticipated that new formulations of antiretroviral drugs and combinations with improved tolerance and convenience may increase the patient and physicians’ willingness to start therapy at an earlier point in the disease.

In regard to the choice of medication with which to begin therapy, several factors need to be considered. Since the number of new drugs continues to multiply, as does information about their benefits and toxicities, it has become increasingly difficult for busy clinicians to stay abreast. There
are several useful resources to assist in that endeavor. The International AIDS Society–USA panel publishes periodic updates to its guidelines. In addition, the Public Health Service (PHS) has established a website that is updated regularly. The expert panel that authors those update guidelines strongly recommends regimens that include either a protease or proteases (indinavir, nelfinavir, ritonavir + saquinavir, ritonavir + indinavir, ritonavir + lopinavir) or a non-nucleoside (efavirenz in the nonpregnant patient) in combination with one of several two NRTI combinations. The USA panel also suggests a combination of two NRTIs with either an NNRTI or a PI boosted with low-dose ritonavir. That panel goes on to state that given the high degree of comparability of the recommended components of these regimens in treatment-naive persons with drug-susceptible virus, the choice of drug centers on acceptability; predicted tolerance; pill burden; comorbid conditions; short-term, mid-term, and long-term adverse event profiles; and successful alternatives in the event the initial regimen fails and drug resistance emerges. The successful outcomes of several “switch studies” suggest that the initial choice of regimen does not preclude safely changing drugs once viral suppression is achieved. There is a great deal of clinical outcome data that support these approaches.

A critical factor to recognize is that often there are poor results with antiretroviral regimens when they are used after an initial regimen has failed. This fact suggests that the first regimen affords the best opportunity for long-term control of viral replication. Because the genetic barrier to resistance is greatest with PIs, many would consider a PI with two NRTIs to be the preferred initial regimen. However, efavirenz (an NNRTI) with two NRTIs appears to be at least as effective as a PI with two NRTIs in suppressing plasma viremia and increasing CD4+ T-cell counts, and many would prefer such a regimen initially because it may spare the toxicities of PIs for a considerable time. However, concerns about efavirenz and teratogenicity, that have been demonstrated in animal models as well as by a case report of a myelomeningocele after in utero exposure in a human make this a poor choice for use in early pregnancy. Thus, although the demonstrated ability of efavirenz in combination with two NRTIs to suppress viral replication and increase CD4+ T-cell counts to a similar degree as a PI with two NRTIs supports a preference for efavirenz over other available NNRTIs, in pregnancy the choice of a different NNRTI may be appropriate. Abacavir, a new NRTI, with two other NRTIs (i.e., a triple NRTI regimen) has been used with some success as well. Such a regimen, however, may have short-lived efficacy when the baseline viral load is >100,000 copies/mL. Using two NRTIs alone does not achieve the goal of suppressing viremia to below detectable levels as consistently as does the other regimens discussed previously and should be used only if more potent treatment is not possible. Use of antiretroviral agents as monotherapy is contraindicated, except when there are no other options or in pregnancy to reduce perinatal transmission, as noted below. When initiating antiretroviral therapy, all drugs should be started simultaneously at full dose with the following three exceptions: dose escalation regimens are recommended for ritonavir; nevirapine (NVP); and in some cases, ritonavir plus saquinavir. Recent data confirm that four drugs are generally no better than three drugs when considering treatment with currently available NRTIs and PIs in treatment-naive patients who are not infected with drug-resistant virus.

In order to determine whether a change in therapy is appropriate, the patient must undergo monitoring for immunologic and virologic response as well as for drug toxicity and acceptability. The aim of antiretroviral therapy remains the maintenance of a plasma HIV-1 RNA level below the limits of detection of the most sensitive assays available commercially (i.e., <50 copies/mL). Effective regimens and high levels of adherence result in a decrease of at least 1.0 log₁₀ copies/mL or 90% per month, and suppression of plasma HIV-1 RNA level to below 50 copies/mL will generally be achieved by 16 to 24 weeks, depending on pretreatment level. After antiretroviral therapy is initiated, the plasma HIV-1 RNA level should be checked relatively frequently (e.g., every 4 to 8 weeks) until it is below the limits of detection and regularly thereafter (e.g., three to four times per year). CD4 cell counts generally should be monitored at the same intervals. Resistance testing is recommended in the setting of virologic failure and ideally should be performed when the patient is taking the failing regimen, which maximizes selective pressure on the virus thus increasing the likelihood that resistance testing will detect any mutations that the patient harbors. Genotypic testing for HIV resistance is preferred over phenotypic testing in most settings because it is faster, readily available, and less expensive; phenotypic testing may be more useful for patients with virologic failure following two or more regimens.

There are several reasons to consider modifying a patient’s regimen. One reason would be adverse drug effects. Intolerance or toxicity frequently occurs within the first several weeks of starting a new regimen. In a previously treatment-naive patient who is not expected to harbor archived drug-resistance mutations, if one offending drug can be identified, changing only that drug in an otherwise successful regimen is virologically safe. With some acute toxic effects such as rash, hepatic dysfunction, and febrile systemic reactions, it may be best to stop all antiretroviral drugs. Therapy also may need to be changed because of treatment failure. Treatment failure may be defined virologically, immunologically (declining CD4 cell count), or clinically (HIV-related disease progression). Viral rebound should be confirmed to ensure that it is not transient (i.e., a blip). The fundamental principle for managing any regimen failure, regardless of how many prior regimens the patient has experienced, is to ensure that at least two, and preferably three, drugs used in the new regimen are likely to have activity based on integration of resistance test results and history of antiretroviral regimen use. In individuals in whom the first regimen fails and who were likely infected
with a drug-susceptible virus, a full assessment of adherence is the first step.

Antiviral medications are used in pregnancy to achieve two goals—to maintain the mother’s health and to prevent mother-to-child transmission (PMTCT) of HIV. In regard to the former, although therapeutic recommendations should not be modified a priori because of pregnancy, a few comments deserve particular mention. The initiation of antiretroviral therapy during the first trimester should be avoided if possible. However, in general, when an HIV-1 infected woman taking effective antiretroviral therapy becomes pregnant, antiretroviral drugs should not be discontinued, though an adjustment in the regimen based on the considerations outlined below may be in order. After the first trimester of pregnancy, the indications for the initiation of therapy are the same as in nonpregnant women with the exceptions noted below. Even if antiretroviral drugs are administered to women for PMTCT of HIV-1, they should be given in combinations intended to be fully suppressive, although some experts will allow for ZDV-only therapy if the viral load is undetectable at the time therapy is initiated (Table 20.3).

Assuming the virus is susceptible, ZDV and lamivudine (3TC) or emtricitabine are the preferred NRTIs. Other NRTIs may be substituted if resistance testing indicates that drug-resistant mutations are present. An increased risk of hepatotoxicity is associated with the use of NVP in pregnancy, especially if initiated in women with >250 CD4 cells/mm³. In women who become pregnant while taking NVP, this risk is substantially lower.

Until more data are available that address concerns about bone formation in utero, tenofovir should be avoided unless resistance testing suggests that its use is advisable. Efavirenz is contraindicated in the first trimester of pregnancy. Nelfinavir has been used extensively in pregnancy, but concerns about its potency make it a less attractive agent. Ritonovir-boosted lopinavir remains an acceptable first-line option, although concerns about dosing have been raised and currently are being addressed.

When possible, ZDV should be used as part of the antiviral regimen. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076, which utilized a regimen of ZDV given during pregnancy and labor and to the newborn for 6 weeks, the antenatal dosing of 100 mg administered orally five times daily was selected on the basis of the standard ZDV dosage for adults at the time of the study. However, administration of ZDV three times daily will maintain intracellular ZDV triphosphate at levels comparable with those observed with more frequent dosing. Comparable clinical response also has been observed in some clinical trials among persons receiving ZDV twice daily. Thus, the current standard dosing for ZDV, whether used as a part of a HAART regimen or as single drug therapy for transmission prevention (discussed below), is 200 mg three times daily or 300 mg two times daily. While it is possible that these dosing regimens may not have equivalent efficacy to that observed in PACTG 076, a regimen of two or three times daily is likely to enhance maternal adherence.

Most data regarding the safety of ZDV have been reassuring. Almost 1,000 children have been tracked for 4 years with no increase in risks of neurodevelopmental delay or carcinogenesis. In regard to monitoring of the mother on ZDV, it only is necessary to measure the blood count and liver functions on a monthly basis. The only abnormality that occurs with any frequency is anemia.

Other NRTIs generally have been 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. By binding to mitochondrial γ-DNA polymerase and interfering with replication, these drugs can induce mitochondrial dysfunction. ddC demonstrates the greatest inhibition of mitochondrial γ-DNA polymerase, followed in order by ddI, d4T, 3TC, ZDV, and abacavir. Clinical disorders associated with mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy, pancreatitis, hepatic steatosis, and lactic acidosis.