**4.1. Therapeutic options**

**•** Rubella serology: both IgG and IgM are evaluated to evidence current or past infection. If there is no evident immunity against rubella, postpartum vaccination is recommended.

**•** Hepatitis B virus surface antigen: to evaluate the presence of disease, since the transmission mechanism and the risk of vertical transmission are similar, and in the event of a synergic

**•** RPR or VDRL: these are nontreponemic tests for syphilis detection. They are highly sensitive but poorly specific. Therefore, if a positive result is obtained, it should be confirmed with a more specific test detecting antibodies against *Treponema pallidum*, such as FTA-ABS (fluorescent treponemal antibody absorption). The presence of such microorganism is

**•** Hepatitis C serology: the purpose of this test is to rule out the carrier status since it is common among HIV-infected patients. It is considered an opportunistic infection and might be

**•** PPD (purified protein derivative) testing for tuberculosis: to evaluate a tuberculosis diagnosis. In HIV-carrier patients, a cutaneous reaction measuring 5 mm is enough to be considered positive (at least 10 mm should be seen in the remainder of patients). Falsepositive results may exist, for instance, in patients previously vaccinated with BCG (bacillus Calmette-Guérin). This infectious association should be considered since it worsens patient

**•** *Toxoplasma gondii* serology: to detect the potential opportunistic infection, mainly with encephalic involvement. In a carrier, a latent *T. gondii* infection may be reactivated as a result

**•** Cytomegalovirus cytology: CMV is the most common viral opportunistic disease in AIDS. It is associated with severe immunosuppression, and the reactivation of a latent disease is

**•** Gonococcus, chlamydia, mycoplasma, and Ureaplasma cultures: since they share in common their mechanism of transmission, other sexually transmitted infections should be

These are prognostic factors for vertical transmission, and they are determinant factors for the appropriate time to initiate ART. They are also parameters for the assessment of the therapeutic

**•** Urine culture: aiming at ruling out an infection of the urinary tract.

56 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

associated with increased vertical transmission [9].

of a deterioration of cellular immunity in these patients.

its usual form of onset. The disease usually has high mortality rates.

Its evaluation is critical to assess resistance to antiretroviral therapy.

effect in disease progression

patient death cause.

prognosis.

ruled out.

response.

*3.4.2. Genotyping*

**3.4. Immunological parameters**

*3.4.1. CD4 T-cell count and viral load assessment (PCR)*

In pregnant HIV carriers, the transmission of the infection to the fetus can occur mainly during delivery (65%), but also during pregnancy and breastfeeding with approximate rates of 35% and 15%, respectively. Such risk for transmission increases with certain factors such as maternal primary infection during pregnancy, intercurrent sexually transmitted infections, decreased CD4 counts, and high viral loads (27). In relation with the latter, and despite the fact that viral loads lower than 1000 copies/ml present a significantly lower risk for vertical transmission, there is no viral load exemption from VT risk. Thus, triple-drug highly active antiretroviral therapy (HAART) regimens have been proven to reach the goal of undetectable viral load levels with a reasonable risk versus benefit quotient, especially during the peripar‐ tum period where the risk of infection of the product of conception is higher. It is during that same period that it is advised to incorporate zidovudine to the regimen, since it has demon‐ strated its efficacy in abbreviated regimens prescribed during the intrapartum and postpartum periods [2, 37-50].

Moreover, the study of the teratogenic risks entailed by the different drugs used in ART regimens has not evidenced a higher incidence of congenital defects than that observed in general population. Likewise the APRI (Antiretroviral Pregnancy Registry International) study on the prevalence of congenital defects was 2.2 per 100 live births when assessing the use of ART at any stage of pregnancy and was 3% when therapy was used during the first trimester. With the exception of efavirenz, which is categorized by the FDA as D, because of its association with neural tube defects, the rest of ARV is categorized as B or C [2]. There are reports in which AZT might be related to an increase of hypospadia rates among the exposed human population, and others where delavirdine might be associated with increased cardiac septal defects in animals [46-49].

The following drugs or combinations should not be indicated during pregnancy: efavirenz, nelfinavir, and the association of d4T (stavudine) and ddI (didanosine). They all share teratogenicity and the risk of toxicity to the mother-child binomial [46-51]. Finally, to optimize the update in side effects, it is essential to fully and continuously report to the competent organizations such as APRI about the possible secondary teratogenic effects and to comply strictly with regulations on the indication for therapy initiation and drug choice according to the stage of pregnancy [46-49, 51].

Although it is true that the first attempt to control VT with a successful pharmacological regime was achieved by the protocol known as ACTG 076, a protocol attaining a decrease in VT from 29% to 5.6% in 2001, new evidence has demonstrated that triple ART was more effective than monotherapy or bitherapy in VT prevention [14, 42-45]. Thus, a protocol that associated biomedical preventive measures (cesarean section and elimination of breastfeeding) with the indication of a combination of three antiretroviral drugs (nucleosidic and nonnucleosidic inhibitors of reverse transcriptase and protease inhibitors, regimens known together as Highly Active Antiretroviral Therapy or HAART) was designed [14, 42-45].

#### **4.2. Antiretroviral therapy during pregnancy**

The purpose of pharmacological therapy during pregnancy is to prevent vertical transmission through the reduction of the viral load in the mother to undetectable levels without resulting in teratogenic effects on the fetus. There are currently 14 commonly prescribed antiretroviral drugs (Table 1) that should be used to customize regimens in which selection is based on the eventual prior treatment of the pregnancy, the status of the disease, the viral load, CD4 cell counts, and the associated toxic and teratogenic effects according to FDA (Tables 1 and 2). Despite other drugs having been demonstrated efficacious in preventing vertical transmission, it is advisable to include the use of zidovudine within the antiretroviral scheme since it is the only drug that has proven efficacy and, most of the times, to be innocuous to the fetus in protocolized regimens (AIDS Clinical Protocol 076-ACTG 076) [2].


**Table 1.** Antiretroviral agent categories according to FDA


**Table 2.** FDA pregnancy categories

29% to 5.6% in 2001, new evidence has demonstrated that triple ART was more effective than monotherapy or bitherapy in VT prevention [14, 42-45]. Thus, a protocol that associated biomedical preventive measures (cesarean section and elimination of breastfeeding) with the indication of a combination of three antiretroviral drugs (nucleosidic and nonnucleosidic inhibitors of reverse transcriptase and protease inhibitors, regimens known together as Highly

The purpose of pharmacological therapy during pregnancy is to prevent vertical transmission through the reduction of the viral load in the mother to undetectable levels without resulting in teratogenic effects on the fetus. There are currently 14 commonly prescribed antiretroviral drugs (Table 1) that should be used to customize regimens in which selection is based on the eventual prior treatment of the pregnancy, the status of the disease, the viral load, CD4 cell counts, and the associated toxic and teratogenic effects according to FDA (Tables 1 and 2). Despite other drugs having been demonstrated efficacious in preventing vertical transmission, it is advisable to include the use of zidovudine within the antiretroviral scheme since it is the only drug that has proven efficacy and, most of the times, to be innocuous to the fetus in

**Generic name FDA category**

Nucleoside reverse transcriptase inhibitors Abacavir C Didanosine (ddl) B Lamivudine (3TC) C

Lamivudine + zidovudine (Combivir) C Stavudine (d4T zalcitabine) C Zidovudine (ZDV, AZT) C Nonnucleoside reverse transcriptase inhibitors Delavirdine C Evavirenz X Nevirapine C Protease inhibitors Amprenavir X Indinavir C Nelfinavir X Ritonavir B Saquinavir B

Active Antiretroviral Therapy or HAART) was designed [14, 42-45].

58 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

protocolized regimens (AIDS Clinical Protocol 076-ACTG 076) [2].

**4.2. Antiretroviral therapy during pregnancy**

**Table 1.** Antiretroviral agent categories according to FDA

#### *4.2.1. ART toxicity and side effects*

One of the aspects that need to be assessed for the selection of a pharmacological therapy is the eventual toxic effect of such medications on the mother-child binomial. Thus, studies have reported that approximately 80% of treated pregnant women developed certain side effects such as anemia, nausea, vomiting, abnormal liver enzyme results, or hyperglycemia [44-49]. As a consequence of the aforementioned, it is essential to know the side and toxic effects of the drugs generally used (Table 3) in order to identify them and act accordingly in the event of using them.

#### *4.2.2. Protease inhibitors*

In the general population, protease inhibitors have been linked to the induction of variable degrees of carbohydrate intolerance. The latter should be considered when prescribing the patient such drugs to the pregnant woman since they might trigger the development of gestational diabetes [44-49].

#### *4.2.3. Nucleoside—reverse transcriptase inhibitors*

There is evidence that nucleoside reverse transcriptase inhibitors may induce mitochondrial dysfunction by virtue of their high affinity for gamma DNA-polymerase found in mitochon‐ dria. Among the drugs of such family that are more intensely related to such adverse effect are d4T (stavudine) and ddI (didanosine) and, to a lesser extent, ZDV (Zidovudine), 3TC (lamivudine), ABC (abacavir), and TDF (tenofir). The association between such type of drugs and lactic acidosis with or without concomitant liver steatosis is also known. Such conditions are more commonly seen in association with the use of d4T (stavudine) (0.8%-1.2%) [44-49]. The clinical picture resulting from such entity is similar to Hellp syndrome, a condition that may or may not be associated to polyneuropathies, fatty liver, myopathies, cardiopathies, and lactic acidosis. Finally, there are literature reports on children from mothers exposed to zidovudine or zidovudine/lamivudine (AZT/3TC) who developed mitochondrial dysfunc‐ tion-related symptoms, a finding that was not observed in the cohort of patients following the ACTG/076 protocol [2].


**Table 3.** Antiretroviral agent toxicity

### **4.3. Opportunity for ART initiation in pregnancy**

Several cohort studies show that the late initiation of ART is associated both with higher VT as well as with longer duration of VT. The latter is based on the fact that when therapy duration was 9.5 weeks, VT was significantly higher than when therapy duration was 16 weeks (*P* < 0.001) [21]. Conversely, in a study conducted at the United Kingdom and Ireland VT was significantly higher among patients with a delayed initiation of therapy (25 + 6 vs. 30 + 1 weeks, <0.001; level of evidence: 2++) [2, 14]. Conditions of ART initiation during pregnancy are listed as follows:


#### **4.4. Choice of drugs to start ART**

Triple ART or HAART (highly active antiretroviral therapy) is the preferred choice. The use of zidovudine (AZT) in association with lamivudine (3TC) 600 and 300 mg per day, respec‐ tively, is recommended for the prevention of HIV vertical transmission. A preparation including both drugs in a fixed drug combination of 300 mg AZT and 150 mg 3TC is commer‐ cially available (grade of recommendation: A). Lopinavir/ritonavir (800/200 mg daily) or saquinavir/ritonavir (2000/200 mg daily) are recommended as a third drug (Grade C recom‐ mendation). The use of nevirapine (NVP) as a third drug may be considered in patients with CD4 T-cell counts lower than 250 cells/mm3 (200-400 mg daily) (Grade C recommendation).

A higher incidence of malformations failed to be demonstrated on 3,000 pregnancies exposed to AZT and 3TC. The 3TC+AZT combination has evidenced a higher efficacy in the prevention of VT than AZT as monotherapy. Cohort studies have reported a reduction in HIV mortality and transmission with the use of AZT+3TC (Level 2+ evidence). There is not enough compa‐ rative evidence of the efficacy of other ARV combinations on VT prevention (Level 2+ evidence) [19, 20, 43, 45].

The use of NVP in pregnant women with CD4 T-cell counts between 250 and 350 cells/mm3 failed to confirm an increase of the risk of suffering severe adverse effects. The benefits of using NVP in pregnant women outweigh the risks (Level 2+ evidence) [19, 20, 43, 45].
