Care and Management

#### **Chapter 7**

## Management Strategies in Perinatal HIV

*Kayla Aleshire and Rima Bazzi*

#### **Abstract**

Current management of perinatal HIV infections and exposures involves the administration of antiretroviral therapy to both the pregnant mother and to her child after delivery. Striving to achieve safe and effective medication management is key in preventing new pediatric HIV infections. Maternal HIV testing and subsequent monitoring can help to identify fetal HIV exposures during pregnancy, maternal nonadherence, insufficient treatment regimens, and otherwise undiscovered exposures during the delivery process. There are several well-constructed guidelines that offer expert references for healthcare providers. This chapter will summarize current recommendations from the United States, with a brief insight into select international guidelines. Although available guidelines provide a structured framework for the healthcare team, there has recently been a significant drive to advance current perinatal management and outcomes.

**Keywords:** pregnancy, perinatal, HIV, antiretrovirals, transmission

#### **1. Introduction**

Nearly 30 years ago, the Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 Study Group identified a reduction in the relative risk of perinatal transmission by almost 70 percent with the use of zidovudine monotherapy [1]. Zidovudine was administered to women starting in their second trimester and continued through the duration of the pregnancy [1]. Additionally, the medication was given to the mother during the intrapartum period, and postnatally to the infants [1]. A few decades later, triple antiretroviral therapy (ART) administered during pregnancy in the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial proved more effective at reducing mother-to-child HIV transmission than with zidovudine monotherapy [2]. The PROMISE trial also demonstrated that there is a concern for transmission through breastfeeding, although this risk may be minimal with the use of ART [3]. Recent statistical evidence estimates that vertical transmission of HIV from mother to child is less than 1% in the United States [4], although it can exceed 10% in some countries [5]. Success in reducing perinatal transmission can presumably be attributed to the advancements in HIV care. Over the last three decades, prevention of mother-tochild transmission (MTCT) strategies have been continuously improving. There are several accepted guidelines that provide step-by-step recommendations for maternal HIV testing, management of acute HIV infection in the pregnant individual, use of

antiretroviral (ARV) medications during pregnancy, the intrapartum period, and post-exposure prophylaxis to the newborn after delivery. The guideline recommendations provide slightly different options for treatment and prevention of perinatal HIV that are vital to controlling viremia in the pregnant mother and the developing child. Despite current information, therapeutic recommendations are more apt to utilize previously accepted regimens in the pregnant and neonatal populations. More recently, there is momentum directed toward conducting research trials with early pregnancies and neonates. Additional information regarding ARV safety and efficacy has the potential to further increase the therapeutic options in these respective populations.

#### **2. Epidemiology**

Nearly 5000 young women across the globe become infected with HIV each week, representing a profound population that warrants attention [6]. Centers for Disease Control and Prevention (CDC) data from the US population indicates that over 70% of new diagnoses in 2019 among females were those of childbearing age [4]. Of women who become pregnant, global estimates suggest that 80% have access to ART [6]. With many pregnant women having access to ARVs, it is important to consider implications in treatment management. Medications should be safe and effective in controlling maternal viremia to prevent newborn acquisition. In addition, HIV testing can help to identify new infections, thus enhancing earlier access to therapy. Over the last decade, new HIV diagnoses in children worldwide have dropped by half [6]. According to CDC statistics in the US population from 2015 to 2019, most children with perinatal HIV exposures in whom seroconversion did not occur were born to mothers who received HIV testing prior to the pregnancy [4]. Within the same period, the rates of acquired perinatal HIV were less than 1% in the United States [4]. Although testing prior to pregnancy is important, women can seroconvert later in the gestational period. Repeat testing should not be neglected as it has been demonstrated that a higher percentage of perinatal transmissions occur after 36 weeks' gestation [7]. In a US Epicenter for HIV, only about 80% of mothers were retested in their third trimester [8]. Furthermore, a study of pregnant women living with HIV in South Africa showed that only 11% of women were receiving all recommended tests throughout the perinatal period [9]. These examples highlight missed opportunities and the underutilization of HIV testing in some areas.

#### **3. Future goals and challenges**

In 2015, the United Nations endorsed a set of global goals to achieve a more promising future for all. One goal presented was to End AIDS by 2030 [10]. Subsequently, the United States advocated for Ending the Epidemic in the US—a plan for a 90% reduction in new HIV infections by 2030 [11]. More specifically, the CDC goal for HIV elimination is to reduce perinatal transmission to an incidence of <1 infection per 100,000 live births and a rate of <1% among infants exposed to HIV [12]. An essential component to achieving these goals is to understand the current approaches to the management of pregnant and pediatric populations and to identify barriers to treatment success. The optimization of medication therapy and performance of pertinent HIV tests are key strategies for preventing perinatal transmission [12–14]. Furthermore, the unique physiologies of neonates and pregnant women present challenges to enhancing medication therapy [15]. The paucity of data in these populations

#### *Management Strategies in Perinatal HIV DOI: http://dx.doi.org/10.5772/intechopen.105451*

limits the recommended medication choices available for treatment and prophylaxis of HIV [12–14]. Currently, recommendations for medication dosing in pregnant women and neonates are often modeled after data obtained from non-pregnant adults or older pediatrics respectively. If efficacy and safety data were more comprehensive for the pregnant and neonatal populations, this would likely have a profound effect on achieving the elimination of MTCT. Additionally, opportunities exist for utilizing HIV testing during pregnancy and surrounding the time of delivery [8, 9]. Adhering to the current recommendations for HIV screening would shorten the time to treatment and potentially reduce viral exposure to the newborn [8].

#### **4. Pharmacokinetic considerations for antiretroviral medications**

The study of pharmacokinetics (PK) seeks to identify if an administered medication possesses the ability to reach therapeutic concentrations in the body, reach the proper site of action to exert its intended effect, and how long the intended effect will remain. Pharmacokinetic drug parameters include the absorption of drugs into the body, metabolism, and the excretion or removal of the drug and waste components from the body. Metabolism can create an active drug from a non-active one or change an active drug into non-active waste products. The products of a medication that result from a metabolic process in the body are termed metabolites. Drug metabolites can be eliminated by the liver or excreted by the kidneys. Another drug parameter to consider is drug distribution. Some medications readily exit the vascular system and distribute into neighboring tissues. Other medications predominantly remain within the vascular compartment. Many medications have a theoretical value, known as the volume of distribution (Vd), that describes this distribution property [16]. Pregnant women and neonates exhibit unique physiological properties that greatly alter medication PK [16, 17].

#### **4.1 Pregnancy**

Maternal physiology changes throughout the gestational period, thus PK parameters of a drug may be increasingly altered as the pregnancy progresses through each trimester. Most ARVs are administered orally and must be absorbed from the gastrointestinal tract. Consider a patient who is suffering from nausea and vomiting during pregnancy. If emesis occurs, then transit time in the stomach for an orally administered medication will be reduced and the medication may not be fully absorbed. If the patient requires antacids to alleviate symptoms, this, in turn, may increase the pH of the stomach. If the administered medication requires a low pH or acidic environment for absorption, an altered pH could affect therapeutic outcomes. Also, during pregnancy, there is a propensity for increased stomach pH, delayed gastric emptying, and slower intestinal motility altering the bioavailability of oral drugs. Enzymes, predominantly in the liver, are responsible for drug metabolism and are altered in the pregnant state. Some have increased activity (e.g., CYP3A4, CYP2D6, CYP2C9, UGT1A4, and UGT1A1/9), while others have decreased activity (e.g., CYP2C19, CYP1A2). This can have significant implications on how much active drug is available, and how fast or slow the administered medication is metabolized in the body. It changes the rate of conversion from active to inactive components or vice versa, depending on the properties of the drug. There is increased renal blood flow and glomerular filtration rate (GFR), resulting in increased elimination of renally-cleared medications, which may

result in shorter half-lives and potential underdosing of those medications. During pregnancy, a woman's body fat, plasma volume, and water volume also significantly increase. In theory, this may create a larger Vd for both lipophilic and hydrophilic medications, requiring higher doses to maintain therapeutic drug concentrations. Albumin concentrations are markedly reduced when pregnancy progresses, and this affects the binding and transport of medications throughout the body. Medications that typically bind well to albumin may be found to have higher free or unbound concentrations, leading to greater efficacy, or an increase of unintended adverse effects. The placenta acts as a membrane where small, lipophilic medications are free to cross, thus medications with these properties may have more influence on the fetus [16].

Medications in the integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) classes have displayed altered PK in pregnancy. A small sample size of pregnant women living with HIV taking the combination of INSTI, elvitegravir, boosted with cobicistat at the approved doses, showed low concentrations of each drug in the third trimester. In most of these women, elvitegravir did not achieve the minimum effective concentration. Additionally, the boosting agent cobicistat was shown to have reduced AUC by about 50% [18]. Similar PK profiles were also observed in an earlier trial by Momper et al. [19]. Of the PI class, both darunavir and atazanavir, boosted with cobicistat have exhibited approximately 50% reductions in plasma concentrations in the third trimester [20]. Treatment regimens utilizing cobicistat as a boosting agent are not recommended in pregnancy by the United States Department of Health and Human Services (DHHS), the European AIDS Clinical Society (EACS), and the British HIV Association (BHIVA) guidelines [12–14]. The PK of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are not expected to be altered during pregnancy [12].

#### **4.2 Neonatal**

Neonatal physiologic considerations are important when selecting safe and effective medications. Once clamping of the umbilical cord occurs, a newborn's body must compensate for life outside the womb. Neonatal development occurs rapidly within the first weeks of life. Throughout this period, the PK of medications can be varied as they are dependent on the maturity of the infant. Gestational age at birth and age after birth both influence pharmacokinetics and the sum of the two ages can be expressed as the postmenstrual age (PMA). Current neonatal dosing recommendations are commonly extrapolated from older pediatric populations and even sometimes from the adult population. Medications are often dosed by PMA and weight; however, this weight-based dosing strategy does not always account for the underexpression of liver enzymes required for drug metabolism and clearance. Full enzyme expression ranges from several days to years (e.g., CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A1). A few enzymes are expressed in the womb but are eventually suppressed after birth (e.g., CYP3A7, FMO1). Medications that require adult enzyme expression for elimination may be overdosed in a newborn still expressing fetal enzymes. Hepatic blood flow rates increase as the newborn develops, so in the early stages of life, medications that are predominantly removed by the liver, exist in the body for a much longer period regardless of enzymatic expression. Weight-based dosing is not a perfect indicator of renal drug clearance either. Although larger infant body weight can be reflective of greater renal function, there is often slower renal development for premature neonates born at less than 34 weeks' gestation. Neonates have lower albumin concentrations which can lead to higher free drug concentrations

#### *Management Strategies in Perinatal HIV DOI: http://dx.doi.org/10.5772/intechopen.105451*

that usually have a high binding affinity to albumin. Neonates have larger water volume, but they have low fat and muscle content. This can be further exaggerated in premature neonates. Lipophilic drugs with a propensity to enter adipose tissue could remain in the vasculature much longer, while hydrophilic drugs may exit the vasculature to a higher degree. Premature infants may also have slightly impaired gastrointestinal absorption [17].

Nevirapine is a medication often used in neonatal prevention of HIV and is largely dependent on CYP liver enzymes for elimination [12–14, 21]. DHHS guideline recommendations for gestational age of greater than 34 weeks up to 1 month are investigational and based on results from the IMPAACT P1115 trial [12, 22, 23]. The PACTG 1043 trial included a two-drug regimen for prophylaxis in infants with a high risk of perinatal exposure. This regimen was composed of standard zidovudine doses and additional fixed-dose nevirapine administered at 0, 2, and 6 days of life, for infants of at least 32 weeks gestational age [24]. The DHHS guidelines categorize this regimen as an option for high-risk exposure in infants born at 32 weeks' gestation or older [23]. A more recent study of premature infants used weight-based nevirapine dosing for post-exposure prophylaxis at a dose of 2 mg/kg/dose on days 0, 2, and 6 of life. This strategy resulted in no clinically significant adverse events. Infants with a gestational age of 28 weeks at birth who received this regimen achieved effective concentrations for prophylaxis and concentrations continued to remain above target concentrations at 2 weeks old. However, for infants greater than 28 weeks' gestational age at birth, plasma concentrations were shown to decline at day 12 [21]. Dosing under the age of 1 month has not been yet approved by the FDA due to insufficient data [23]. Though there is limited evidence for drug approval in the US, these trials illustrate the variability of pharmacokinetics in the neonate and highlight the necessity for additional studies for neonatal ARV dosing recommendations.

#### **4.3 Drug-drug interactions**

People living with HIV should be exposed to adequate concentrations of ARVs to achieve and maintain virological suppression. After considering the PK and pharmacodynamics (PD) of pregnancy, attention must be directed to important potential drug-drug interactions (DDIs) involved with HIV management in pregnancy. DDIs can occur at any step of the pharmacokinetic process where drug parameters are affected. As mentioned earlier, this may include absorption, distribution, metabolism, and elimination. DDIs can result in an increased concentration of ARV or concomitant drug, leading to potentially adverse effects. Alternatively, DDIs can lead to decreased ARV concentrations resulting in subtherapeutic concentrations and potential development of resistance.

Drug absorption can be affected by transit time in the stomach, chelation, or changes in pH. As discussed earlier, transit time can be reduced due to nausea and vomiting during pregnancy, slower intestinal motility, and delayed gastric emptying. Chelation occurs when components of an INSTI's chemical structure bind to polyvalent cations present in other medications such as calcium supplements, multivitamins, iron products, or antacids. The resultant chelated compounds are less likely to be absorbed and thus exhibit potential for reduced efficacy of the INSTI. As medications containing polyvalent cations are commonly used during pregnancy, mindful separation of these products from an INSTI-containing regimen is critical. As administration directions for each INSTI and polyvalent cations vary, in general,

the recommendation is to give the INSTI about 2 h prior to any of the aforementioned medications to allow absorption to occur. If the supplement is administered first, then the INSTI is advised to be administered 4–6 h afterward. Some ARVs require an acidic environment for complete absorption. Acid-reducing agents such as proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), or antacids will influence the absorption of these drugs. Ritonavir-boosted atazanavir is a PI recommended to be given during pregnancy. If a PPI or H2RA medication is utilized, it should be given about 12 h apart from ART. Rilpivirine, an NNRTI, should be given with food and separated from the H2RA. However, PPIs are specifically contraindicated with rilpivirine [12].

Hepatic metabolism can be influenced, not only by the pregnant state but also by select ARVs that are administered. PIs and their boosters inhibit many metabolizing enzymes, resulting in reduced elimination and increased plasma levels of other medications. Ondansetron is used to alleviate nausea and is a substrate of hepatic enzymes. Administration with PIs and their boosters can increase the side effects of ondansetron, notably cardiac prolongation of the QT interval. Clinical monitoring including electrocardiogram (ECG) assessments is recommended for prolonged concomitant drug therapy. Fentanyl plasma concentrations can be significantly increased by ritonavir, however, intrapartum epidural administration of fentanyl over a short period of 24 h has been suggested to be safe [12].

Although boosted atazanavir is expected to increase the concentrations of the NRTI tenofovir disoproxil fumarate (TDF), it is also apparent that TDF causes lower plasma concentrations of atazanavir (ATV) in the third trimester if the agents are combined in a regimen [12–14]. The BHIVA guidelines recommend that if this combination is used then therapeutic drug monitoring may be considered. They inform that it is not necessary to adjust the dose of ATV, when used in combination with TDF, but that dosage adjustments may be made on a case-by-case basis [14]. Furthermore, the combination of ATV and TDF is not recommended with additional use of an H2RA. If these three agents are still utilized concomitantly, then it is further recommended adjust the ATV dose from 300 to 400 mg daily [14]. The DHHS guidelines also do not recommend ATV in combination with TDF and an H2RA in a treatment experienced pregnant patient. They also do not instruct providers to adjust the dose if it is utilized. Instead, they inform that the increased dose reaches adequate plasma concentrations, and they provide recommendations from the FDA package insert for atazanavir. The Federal Drug Administration (FDA) label recommendation is that increased atazanavir dosing may be utilized if used in combination with both TDF and an H2RA [12]. All guidelines recommend that ATV is to be boosted with ritonavir during pregnancy [12–14].

Health care providers should consider that concentrations of methylergonovine, a medication used for post-partum hemorrhage, can be altered by ART. PIs and their boosters can increase the effect of methylergonovine resulting in increased uterine smooth muscle tone, posing risk for uterine tetany. Patients on ART containing PIs or boosting agents should not be prescribed methylergonovine unless oxytocin or misoprostol are not available. In contrast, methylergonovine can be reduced by medications in the NNRTI class, such as rilpivirine or efavirenz as they induce liver enzymes and increase the elimination of methylergonovine [12]. Due to the complexities of DDIs and ARVs, and the dire consequences of subtherapeutic ARV concentrations leading to potential resistance, health care prescribers are encouraged to refer to the product insert, treatment guidelines, online DDI websites or to consult with an HIV pharmacist for further assistance.

#### **5. Antiretroviral selection and initiation in the treatment naïve pregnant person living with HIV**

One of the major goals of therapy in HIV treatment during pregnancy is to reduce the risk of transmission to the fetus. Since the initial use of zidovudine as monotherapy throughout pregnancy and intrapartum, it has been well established that the risk of perinatal transmission can be decreased when viral suppression is achieved [1]. When choosing a new regimen for a treatment naïve pregnant patient living with HIV, it is important to consider DDIs, PK, and side effects that may influence treatment efficacy or incur harm to the fetus.

Recommendations for the treatment of HIV during pregnancy vary slightly between the European AIDS Clinical Society (EACS), British HIV Association (BHIVA), and United States Department of Health and Human Services (DHHS) guidelines and preferred agents are summarized below (e.g., **Table 1**). ART is recommended for all pregnant women with HIV. The timeframe in which to initiate treatment in a pregnant woman living with HIV who is not currently on therapy is debated. If a pregnant woman is newly diagnosed with HIV, treatment should not be delayed according to DHHS and EACS, regardless of the patient's viral load, CD4 count, or pending resistance genotype results. In contrast, BHIVA recommends that treatment be started preferably during the second trimester, although it is permitted to start earlier if the patient's viral load exceeds 100,000 copies/ml or CD4 is less than 200 cells/mm3 . BHIVA also recommends that treatment not be initiated before HIV resistance genotype results are reviewed, except for women who present to care in the third trimester.

Collectively, the guidelines recommend a dual NRTI backbone in combination with a third agent as the choice treatment. The selected agents preferred in each of the dual NRTI backbones, and the third agent differ slightly among the guidelines. The guidelines share recommendations for an NRTI dual backbone of abacavir/lamivudine (ABC/3TC) and tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) with the exclusion of any NRTI combination that includes zidovudine (ZDV). Zidovudine- based therapy is no longer preferred in the adult population due to concerns about toxicity, so aside from its short-term use in intrapartum care and infant prophylaxis, it has become an alternative agent. HLA-B\*5701 testing


*\*RAL 400 mg and DVR/r 600 mg/100 mg are recommended to be dosed twice daily. + TAF should only be initiated after 14 weeks' gestation according to EACS guidance.*

#### **Table 1.**

*Preferred ARV agents in the pregnant person living with HIV.*

should be done prior to initiation of any regimen containing abacavir (ABC) to rule out hypersensitivity to the drug.

Regarding the tenofovir formulation, DHHS recommends that either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) may be used as a preferred agent. EACS includes TAF among their preferred NRTI backbone options as well, but TAF is an alternative agent according to the BHIVA guidelines. BHIVA and EACS indicate that if TAF is to be included in a regimen, it should be used after 14 weeks of gestational age, due to its unevaluated safety and efficacy within the first trimester of pregnancy. Contrastingly, the DHHS panel does not place gestational age limits on the drug as the guidelines suggest the two agents have similar efficacy and safety profiles when used in pregnancy [12–14].

INSTIs have the ability to suppress viral load quickly and efficiently. As for the third agent comprising a complete regimen, INSTIs are preferred as indicated in both EACS and DHHS guidelines [12, 13]. In contrast, BHIVA suggests that INSTI regimens are to be reserved for pregnant patients presenting with high baseline viral loads of greater than 100,000 copies/ml or those with current ART that have failed to achieve adequate viral suppression [14]. Dolutegravir (DTG) is the INSTI of choice across the guidelines, though DHHS and EACS additionally include raltegravir (RAL) [12, 14]. It is important to note, however, that if raltegravir is used, it must be dosed twice daily in pregnancy, as there is insufficient information regarding the use of daily dosing of raltegravir during pregnancy [12]. In contrast to the US guidelines, both European guidelines state for dolutegravir to be included in a regimen, it should be started preferably after 6 weeks of gestation [13, 14]. This restriction is due to the previously proposed association of infant neural tube defects with dolutegravir use in pregnancy [25]. The guidelines further express that those pregnant women living with HIV should be fully informed prior to making the decision to initiate or switch therapy to dolutegravir [13, 14].

Although INSTIs are preferred agents to be included in a three-drug regimen within the EACS and DHHS guidelines, all three guidelines additionally recommend the use of a PI as the third ARV in a regimen [14]. Within the DHHS and BHIVA guidelines, ritonavir-boosted atazanavir (ATV/r) is recommended as a first-line agent from the PI class [12, 14]. Along with boosted atazanavir, DHHS also includes ritonavir-boosted darunavir (DTV/r) with twice-daily dosing as an appropriate third agent in a first-line treatment regimen [12]. In contrast, EACS lists DRV/r as a preferred agent only when used with a tenofovir-based NRTI backbone, not with ABC/3TC. Boosted atazanavir is not included in the EACS preferred regimens for pregnant patients initiating therapy [13]. The preferred boosting agent is ritonavir as regimens boosted with cobicistat have resulted in treatment failure during pregnancy, as mentioned previously [12–14].

Notably, the BHIVA guidelines also recommend efavirenz, an NNRTI, as an additional preferred agent to be used in combination with a dual NRTI backbone. This is due to its historically extensive use during pregnancy, thereby possessing the most data for its efficacy and safety [14]. In opposition to this BHIVA recommendation, DHHS and EACS both indicate that efavirenz is an alternative option for use in an ARV drug regimen during pregnancy [12, 13]. It should be carefully considered that NNRTI agents are not active against HIV-2 and so should be avoided in this population [12–14].

#### **6. Testing and monitoring HIV clinical status in pregnancy**

The DHHS guidelines recommend that all women be tested for HIV with each pregnancy at their earliest visit with their Obstetrician (OB). They further

#### *Management Strategies in Perinatal HIV DOI: http://dx.doi.org/10.5772/intechopen.105451*

recommend repeat testing during the third trimester, even if the initial test was negative for mothers who may have a heightened risk of acquiring HIV. These women are identified as those who receive care in facilities or jurisdictions that have an increased incidence of HIV, women with behaviors that impose a high risk of HIV acquisition, or who present at any time during the pregnancy with another sexually transmitted infection (STI). Additionally, there are select states within the US that require a third trimester HIV test to be performed. If a mother presents in labor and her HIV status is unknown, HIV testing should be expedited with results available within the hour, to help determine if additional measures should be taken to prevent transmission to the child. If there was no HIV test conducted at any time during the pregnancy or during labor, it is advised that a mother is tested immediately postpartum to further determine any risk to the child. The HIV test that is recommended is a combination antibody/antigen test. Since it takes time for complete antibody development in response to an infection, this test could produce a false negative during the first 14 days of an acute HIV infection. Therefore, if an acute HIV infection is suspected, an HIV-1 RNA PCR test (viral load) is recommended as it can detect maternal viremia as early as 10 days post-exposure [12].

Several studies have demonstrated that maternal HIV testing may be underutilized [8, 9]. In a study conducted in a US epicenter for HIV, about 20% of women did not receive a second HIV test during their 3rd trimester. This is very unfortunate, as it could lead to delays in detection of previously unknown maternal HIV, thus resulting in delays to ARV access to the mother and to her child after birth.

One focus for improvement could be increasing provider awareness. Providers should be aware of the local prevalence of HIV infections and recommendations for HIV screening during all trimesters. Furthermore, conducting nonbiased social and sexual health histories during pregnancy would be useful to identify high-risk women who may benefit from a repeat HIV screening test in the third trimester [8].

If a pregnant mother has been living with HIV or is newly diagnosed during the pregnancy, there are additional testing recommendations for monitoring the clinical status of HIV, as well as the risk of transmission to the child. An HIV-1 RNA test should be conducted at the initial OB visit for any woman living with HIV. This helps to assess baseline viremia and establish immediate goals of care. The viral load is recommended to be repeated after 2–4 weeks if therapy is initiated or adjusted. Furthermore, once stabilized on an antiretroviral regimen, the viral load should be performed every month until viral suppression is achieved, then performed every 3 months thereafter. There should be an additional viral load conducted between 34 and 36 weeks' gestation in anticipation of delivery. This viral load will help to determine treatment measures that need to take place during the intrapartum and postpartum periods to prevent transmission. The CD4 count is not as critical to monitor throughout pregnancy if a mother has been previously stable on a regimen for at least 2 years. In this scenario, an initial CD4 collected at the first visit will suffice. However, if a mother was not virally suppressed on her ARV regimen, or has newly switched or initiated a ARVs during pregnancy, then CD4 testing should be conducted every 3 months until delivery. Antiretroviral resistance testing recommendations are similar to those in non-pregnant adult patients. As such, it is recommended that resistance testing be performed prior to initiation of ART, upon modification of a regimen, or if there is inadequate control of the viral load [12]. Resistance testing should not cause delays in care; thus, a clinician does not need to wait for the results of the genotype in order to start therapy. The therapy can be adjusted when the genotype results are available.

Based on monitoring during pregnancy, the child's risk for HIV acquisition can be categorized. The maternal viral load is the most important criterion for defining risk. Perinatal transmission can occur in utero at any time during the gestational period. It is especially important to assess the viral load late in the pregnancy, nearest to the time of delivery, as it is presumed that this time period is where most transmissions occur [7]. If a viral load is undetectable just prior to delivery, it is suggested that the infant is at low risk for the acquisition of HIV [12]. However, if the viral load is high during the late gestational period, the infant's risk is heightened [7, 12]. Other factors to consider in determining MTCT risk are the timing of the mother's antiretroviral treatment initiation, adherence to ARV medication throughout the pregnancy, and acute HIV infection during the pregnancy or during the breastfeeding period [12].

#### **7. Antiretroviral selection for the intrapartum period**

The PACTG 076 trial led to the recommendation of IV zidovudine during labor [1]. This initial recommendation preceded the current recommendations for women living with HIV to be on triple ART throughout pregnancy and as close to their normal schedule as possible even during the labor and delivery period [2, 12–14]. Thus, if the viral load is less than 50 copies/ml, the DHHS, BHIVA, and EACS guidelines agree that a pregnant mother on effective ART may proceed with a spontaneous vaginal delivery and the addition of IV zidovudine is not warranted [12–14]. However, if the viral load is not suppressed, the guidelines all support the use of IV zidovudine at the time of delivery. Zidovudine is administered as an initial loading dose of 2 mg/kg/h over the first hour of treatment, followed by a continuous infusion of 1 mg/kg/h until clamping of the umbilical cord has been performed [1, 12–14]. In the EACS guidelines, the threshold for when IV zidovudine is required is a viral load above 50 copies/ml or an unknown HIV status [13]. Contrastingly, BHIVA and DHHS provide that viral loads within the range of 50–1000 copies/ml do not necessitate IV zidovudine, although other factors, such as adherence, are to be considered when making the decision whether to initiate zidovudine [12–14]. Any time that a pregnant patient's HIV status is unknown or newly diagnosed during delivery, the guidelines agree that IV zidovudine should be initiated [12–14]. BHIVA furthermore recommends that the mother receive a single oral dose of nevirapine followed by oral zidovudine, lamivudine, raltegravir dosed twice daily, and IV zidovudine administered during delivery. BHIVA also indicates that if the infant is unlikely to take oral medications due to prematurity or other reasons, consider the addition of an oral double dose of TDF to the maternal oral regimen received prior to delivery [14]. The maternal viral load also influences the mode of delivery. Scheduled cesarean section (c-section) is strongly recommended by DHHS guidelines if the mother's viral load near delivery is >1000 copies/ml or unknown [12]. The urge for scheduled c-section is expressed by BHIVA guidelines with >400 copies/ ml [14]. This threshold is further reduced in the EACS recommendations, at a viral load of 50 copies/ml or greater [13]. All c-sections are recommended to be scheduled at 38 weeks' gestation in hopes that the mother will not yet go into active labor [12–14].

#### **8. Antiretroviral selection in the infant exposed to HIV**

In order to determine the appropriate ARVs to initiate in the newborn who is born to a mother living with HIV, a clinical assessment of transmission risk needs to be

#### *Management Strategies in Perinatal HIV DOI: http://dx.doi.org/10.5772/intechopen.105451*

performed. Risk stratification dictates whether a newborn will receive post-exposure prophylaxis (PEP) or an empiric initial ART. This stratification of risk is based on several factors. As discussed previously, it is important to appreciate the mother's viral load at or near the time of delivery. As a reflection of the viral load, it should be determined if the mother received the appropriate intrapartum antiretroviral medication(s). The mode of delivery should be noted. If the mother delivers via a spontaneous vaginal delivery, an assessment of the timing of placental rupture of membranes (PROM) is also an important consideration [12]. A duration of membrane rupture of greater than 4 h prior to delivery increases the chance of perinatal HIV transmission [26].

The recommendations for PEP of infants born to mothers with HIV are similar among both BHIVA and DHHS guidelines and are summarized below (e.g., **Table 2**) [12, 14]. BHIVA guidelines divide perinatal exposures into very low risk, low risk, and high risk [14]. The DHHS guidelines divide exposures into three groups as well, defined as low-risk, high-risk, and presumed newborn HIV infection [12]. In contrast, EACS defers PEP recommendations to local guidelines and only offers treatment recommendations for infants diagnosed with HIV [13].

According to the BHIVA panel, ARVs should be started within 4 h of delivery [14]. The DHHS broadens this window slightly to within 6 h of delivery [12]. The first risk category in the BHIVA guidelines is very low-risk and an infant is assigned this category when all the following criteria are met: the mother has been on appropriate antiretroviral therapy for greater than 10 weeks, had two documented HIV-1 RNA <50 copies/ml during pregnancy which were at least 4 weeks apart, and HIV-1 RNA <50 copies/ml at or after 36 weeks. Only 2 weeks of zidovudine monotherapy is indicated for such an infant [14]. The lowest risk category listed in the DHHS guidelines is the low-risk category, where the infant's mother received appropriate ART during pregnancy, and achieved viral suppression within 4 weeks, with no adherence concerns. In this scenario, a low-risk infant should receive 4 weeks of zidovudine monotherapy [12]. The BHIVA panel also recommends 4 weeks of zidovudine monotherapy for an infant in their low-risk category. An infant is considered low risk if the previous criteria are not met for very low risk, but maternal viral suppression is achieved at or after 36 weeks for a term baby, or near the delivery of a premature


*\*RAL should be considered for infants at high risk of perinatal HIV-2 transmission because HIV-2 is not susceptible to NVP [12]. In infants exposed to HIV-2, ZDV/3TC/RAL should be initiated until expert advice is available [14]. +Duration of therapy depends on patient-specific risks and expert advice is recommended [12]. Note: EACS defers PEP recommendations to local guidelines [13].*

#### **Table 2.**

*Antiretroviral post-exposure prophylaxis in the infant exposed to HIV.*

baby [14]. According to the DHHS guidelines, if a mother did not receive antepartum therapy, only received intrapartum ARVs, viral suppression was not achieved within 4 weeks of delivery on a regimen, or an acute or primary HIV infection was discovered during pregnancy, the infant would fall within the high-risk category [12]. For those in this DHHS high-risk category, presumptive HIV therapy should be initiated with at least 6 weeks of zidovudine and 2–6 weeks of lamivudine and nevirapine. One may also alternatively administer zidovudine, lamivudine, and raltegravir [12]. The BHIVA panel recommends that if maternal viral suppression was not achieved by the day of birth, viral load is unknown, or there is adherence uncertainty, this is considered high-risk and a 4-week course of combination PEP is indicated consisting of zidovudine, lamivudine, and nevirapine [14]. The DHHS panel recommends presumptive therapy for those newborns who are clinically suspected to have acquired HIV infection. This is when mothers with unconfirmed HIV status have at least one positive HIV test at delivery or postpartum or there is a positive HIV antibody test for the newborn [12]. The three-drug ART recommendations are similar in the DHHS high-risk category and the presumptive treatment category. The doses prescribed may change slightly with confirmed HIV infection [12]. For confirmed newborn HIV infection, EACS recommends that the infant be started on a three-drug combination regimen consisting of the dual NRTI-backbone zidovudine and lamivudine with the third agent options of lopinavir/ritonavir, nevirapine, or raltegravir [13].

#### **9. Testing in the infant exposed to HIV**

Once a child is known to have perinatal exposure, seroconversion must be ruled out or identified with HIV testing. In the neonate, antibody/antigen tests cannot be recommended. The general concept of passive immunity ensures that a mother protects her newborn infant from infections, by passing along her own antibodies through the placenta until the baby's own immune system can develop. The 4th generation antibody/antigen combination test is often performed for the adult population; however, this test could provide false results in an infant born to a mother living with HIV due to the presence of maternal antibodies in the infant's blood. Due to the underdeveloped immune system of the infant, the antigen test would not be as sensitive as virologic testing, thus it is important to test for HIV using virologic HIV RNA or HIV DNA Nucleic Acid Amplification Testing (NAAT). If a non-breastfeeding infant was exposed intrauterine or during the labor process, then either NAAT is recommended at birth and should be repeated 2–6 weeks after the cessation of PEP medications [12, 23]. According to DHHS protocol, infants born at high-risk for perinatal transmission should be tested as soon as possible and before initiation of ART so as not to skew test results. Despite this recommendation, however, ART should never be delayed [12]. A positive test within the first 2 days likely reflects an early intrauterine exposure. In non-breastfeeding infants who test negative during their first week of life, but test positive upon repeat testing, it can generally be assumed that they were exposed intrapartum, or later during the pregnancy [7].

#### **10. Breastfeeding considerations**

Perinatal transmission of HIV can occur in utero, labor, and delivery, or during the breastfeeding period. There are concerns about transmission risk to the infant


#### **Table 3.**

*Summary of guideline recommendations for persons living with HIV who are breastfeeding.*

through breastmilk versus the benefits that breastmilk can provide. These concerns differ between high-income (HIC) and low-middle income countries (LMIC). It can be estimated that postnatal vertical transmission rates during breastfeeding range from 5 to 20% without intervention [27]. HIV viral load is collected from plasma samples for monitoring, however, there is less information on viral load in breastmilk. The Undetectable = Untransmittable (U = U) concept derived from the PARTNER study provides that people living with HIV who are on ARV and are undetectable cannot sexually transmit the virus to their partners [28]. There is interest in expanding the U = U concept to breastfeeding mothers on ART. Part of the PROMISE study compared postpartum ARV prophylaxis in mother-baby pairs where breastfeeding occurred. The pairs were randomized to one of two ARV prophylaxis arms where either maternal ART versus daily infant NVP was administered [3]. In the primary analysis, the same number of infants were infected with HIV-1 from each arm. Thus, there was no difference between arms with vertical transmission and infant HIV-free survival at 24 months of age was high in both arms [3]. Importantly, the trial was not able to demonstrate a difference between arms due to the low degree of acquired infections. This demonstrates that both regimens were very effective in preventing transmission [3]. However, a secondary analysis of the trial did result in two infants in the maternal ART arm acquiring HIV despite maternal viral loads of less than 40 copies/ml [12]. Although U = U in the setting of breastfeeding is still undetermined, data from women in LMIC and emerging data from HIC show the transmission risk is low in the setting of strict adherence to ART and being virally suppressed [29, 30]. Although transmission risk is low, it is still possible. A summary of the breastfeeding recommendations by each guideline is provided in **Table 3** [12–14].

#### **11. Modern considerations for ethics and research**

In 2018, clinical alarm spread across the globe after results from the Tsepamo surveillance study in Botswana suggested a relationship between dolutegravir exposure at conception and infant neural tube defects [25]. At the time, Botswana had switched from efavirenz-based to dolutegravir-based first-line therapy for the adult treatment of HIV [25]. Dolutegravir is a vivid example of how newly approved medications become available to the majority of women of child-bearing age, despite having never been tested in the pregnant population. Fortunately, by 2020, additional data collection on the prevalence of neural tube defects in infants exposed to dolutegravir at the time of conception stabilized the previously alarming numbers to less than 0.2%. This was comparable to the 0.11% prevalence rate of neural tube defects in infants of mothers who were not on dolutegravir at conception [31]. As discussed earlier, dolutegravir is now recommended as a preferred agent by the DHHS guidelines for women of childbearing potential [12]. However, it is not recommended until after the first trimester by other panels [13, 14]. The dolutegravir-scare sparked an international momentum for modifying the ethical considerations surrounding drug research and pregnancy [32]. The Tsepamo study highlights the importance of conducting earlier and more frequent trials including large study populations of pregnant women.

The intricate nature of balancing maternal benefit versus fetal harm has been a long-standing phenomenon in the field of drug research. This balancing act teeters between providing effective therapy for a pregnant mother while preventing harm to her developing child. For a long time, the scales tilted in favor of omitting useful medications, thus avoiding potential harm to the fetus. This one-sided sway reflects the perception that the fetus is so vulnerable to harm that providing appropriate maternal treatment for an array of maternal medical conditions does not provide sufficient benefit [15, 32]. This view also assumes that what may be safe for the fetus is also most appropriate for the mother [33]. First, this idea is an underrepresentation of how effective maternal medication management, directly improving maternal health, can indirectly result in improved pregnancy outcomes for the child-in-utero [33]. Second, this concept neglects a pregnant mother's ability to make decisions for herself and for her own child [33, 34]. Instead, it leaves both providers and their pregnant patients to make less informed decisions from the limited academic information available to them [33–35]. Third, it results in more off-label use in the post-marketing pregnant population rather than use in carefully conducted and monitored trials [33, 34]. Fortunately, HIV is one chronic medical condition for which there have been considerable efforts through the years to obtain pregnancy data [32, 33]. This can be largely attributed to organizations such as the Pharmacokinetics of newly developed ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network [36, 37]. The IMPAACT network was originally established 16 years ago as the Pediatric AIDS Clinical Trials Group (PACTG) and the Perinatal Scientific Working Group of the HIV Prevention Trials Network (HPTN) joined forces to end the HIV epidemic with a special focus on pediatric and pregnant populations. The IMPAACT Network is a global collaborative effort based in the United States to conduct quality research [37]. The PANNA study is a European Network that collects pharmacokinetic data in pregnant women and aims to obtain information on new antiretroviral medications with little to no information on this population [36]. Although there is some clinical research information available for antiretrovirals in pregnancy, it is a research area with a great opportunity [15, 32–34]. Generally, pregnancy data for ARVs are obtained when women living with HIV become pregnant on a stable ART, and the decision is made to continue the regimen throughout the pregnancy. Aside from the limited pregnancy data available, guideline recommendations are often based on extrapolations from the non-pregnant adult population. Most research today does not present separate PK data for men and

#### *Management Strategies in Perinatal HIV DOI: http://dx.doi.org/10.5772/intechopen.105451*

women, therefore extrapolation can be difficult to draw from women of childbearing potential to women who become pregnant when it often includes male data [16].

The agencies that influence drug approval in the United States are the Federal Drug Association (FDA) and DHHS. There are drug research regulations that were originally designed to protect human rights in drug trials, including the protection of women of child-bearing potential, pregnant women, and their children [38, 39]. Additionally, there are provisions for these populations in DHHS protocols [38]. Although adherence to these DHHS protocols is not mandated in FDA-conducted drug trials, the FDA still has recommended the DHHS guidance to be followed [38]. Historically, regulations have emphasized much effort in protecting the fetus, and pregnant women are often excluded from drug research trials [39]. If there was a shift in focus from protecting women and their unborn children by omitting them from drug trials to including them, there could be great potential. This could provide more available treatment options and identify early in the gestational period if medications are not effective. There would be information on how to adjust medication doses during pregnancy [33, 34]. This shift in focus can also be applied to the neonatal population. If there were additional information on the PK and PD of ARVs in the neonatal population, there could be more successful outcomes. Luckily, there has recently been a turning point in history. In 2017, the Third Conference on Antiretroviral Drug Optimization (CADO 3) was held to discuss the implications of newer antiretroviral agents to current standards of care, and the re-sequencing of first-, second-and third-line therapies for the future [40]. Shortly following this, the statistical results of neural tube defects discovered by the Tsepamo study raised a global alert [25] and the FDA issued draft guidance for reconsidering the ethics and science behind drug research regulations for the pregnant population [38]. The World Health Organization (WHO) also held a pediatric antiretroviral drug optimization (PADO) meeting in which the regulatory framework for research in pregnancy was determined to be outdated [32]. The CADO and PADO experts, among many others, proposed adjusting the drug approval timeline to shorten the delay of access to new antiretroviral medications for pregnant women [32, 40]. A WHO-IMPAACT-led workshop was held to address evidence gaps and identify opportunities for change. The workshop included experts from the fields of research and pharmacokinetic studies, regulatory agencies, public organizations, and stakeholders. Their consensus statement was published in 2019 which proposes earlier conducted research trials and the barriers that need to be addressed to conduct these trials [15]. In July 2020, The PHASES Working Group - Pregnancy and HIV/AIDS: Seeking Equitable Study issued a 12-step recommendation pathway for the industry [33, 34]. It stressed evidence gaps in dosing, fetal safety, and maternal outcomes and identified that in order to close these gaps changes needed to be made to the concept of ethics in pregnant women. Their call-to-action plan sought to address the inequities presented to pregnant women in access to first-line therapies, respecting pregnant women by allowing them to choose a therapy that would enhance their own health outcomes, and protection from drug-related risks when using medications "off-label" because there is no pregnancy data [33, 34]. At the end of 2021, the World Health Organization (WHO), the IMPAACT Network, and the International AIDS Society launched another "Callto-Action" campaign [35]. This was a call for the inclusion of the female voices of women living with HIV and to change from viewing pregnant women as a vulnerable population to a population with many intricacies that should be addressed. This call to action speaks to stop protecting patients by excluding them and to instead protect them by including them [35].

#### **12. Conclusion**

The ethical considerations for pregnancy and neonatal populations are beginning to change. The focus is shifting in the direction of protecting these populations by conducting medication research trials that are inclusive. There are many advancements in HIV management, however, the field continues to evolve with more research and practical world experience. As more data unfolds, this may lead to more drug therapy options for the management of perinatal HIV. In turn, it may result in the use of safer and more effective ARVs in the pregnant and neonatal populations. With the availability of more reliable ARV options, utilization of these medications, and adherence to recommended HIV screening guidelines, there is more potential to reduce the transmission of HIV from mother to child, moving the HIV field toward achieving ending the HIV epidemic globally.

#### **Acknowledgements**

We would like to acknowledge our dear friend and colleague in the field of HIV Jean C. Lee, PharmD, AAHIVP for her invaluable support and feedback for our chapter.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Kayla Aleshire and Rima Bazzi\* PharmD AAHIVP, Beaumont Health, Dearborn, USA

\*Address all correspondence to: rima.bazzi@beaumont.org

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 8**

## HIV Infection and Oral Manifestations: An Update

*Ricardo Roberto de Souza Fonseca, Rogério Valois Laurentino, Luiz Fernando Almeida Machado, Carlos Eduardo Vieira da Silva Gomes, Tatiany Oliveira de Alencar Menezes, Oscar Faciola Pessoa, Aldemir Branco Oliveira-Filho, Tábata Resque Beckmann Carvalho, Paula Gabriela Faciola Pessoa de Oliveira, Erich Brito Tanaka, Jorge Sá Elias Nogueira, Douglas Magno Guimarães, Marcelo Newton Carneiro, Paula Mendes Acatauassú Carneiro, Aluísio Ferreira Celestino Junior, Patricia de Almeida Rodrigues and Silvio Augusto Fernandes de Menezes*

#### **Abstract**

Human immunodeficiency virus (HIV) causes a complete depletion of the immune system; it has been a major health issue around the world since the 1980s, and due to the reduction of CD4+ T lymphocytes levels, it can trigger various opportunistic infections. Oral lesions are usually accurate indicators of immunosuppression because these oral manifestations may occur as a result of the compromised immune system caused by HIV infection; therefore, oral lesions might be initial and common clinical features in people living with HIV. So, it is necessary to evaluate and understand the mechanism, prevalence, and risk factors of oral lesions to avoid the increase morbidity among those with oral diseases.

**Keywords:** HIV, acquired immunodeficiency syndrome, immune deficiency disease, oral cavity, oral manifestations, periodontal disease

#### **1. Introduction**

Since the twentieth century, the human immunodeficiency virus (HIV) has been a global public health problem, and for about 40 years, the structural aspects,

pathogenic mechanisms, forms of transmission, and cycle of infection have continued to be studied in order to reach a detailed understanding of the infection of this virus in its carriers [1–3], especially in key populations such as men who have sex with men, transgender people, sex workers, people who inject drugs, indigenous people, and prisoners [4–11], in order to seek to develop solutions for immunosuppression caused by HIV, such as antiretroviral therapies and even effective vaccines [12–14].

HIV is a member of the order *Ortervirales*, family *Retroviridae*, subfamily *Orthoretrovirinae*, and genus *Lentivirus*, which are currently grouped into two types, HIV-type 1 (HIV-1) and HIV-type 2 (HIV-2) and infections caused by HIV. Lentiviruses generally have a chronic aspect of development, with a long period of clinical latency and persistent viral replication, and cause progressive immunosuppression in their hosts [2, 15–17]. Both HIV-1 and HIV-2 will infect specific cells of the immune system, such as CD4+ T lymphocytes, macrophages, dendritic cells, and mucosal lining cells such as vaginal, anorectal, and oral, which will later spread to regional lymph nodes and, consequently, into the bloodstream, which will cause changes in the development and function of the immune response [18–23]. Although certain differences can be seen between the two types, such as HIV-2 greater predilection for central nervous system infections and a lower virulent potential than HIV-1 [24–28].

In practice, HIV transmission requires direct exposure to blood or fluids, or secretions contaminated with areas such as skin or mucous membranes with mechanical trauma or discontinuity of integrity, either by punctures with needles or cuts with cutting instruments or abrasions of mucosal tissues during sexual relations or the vertical route [29, 30]. Furthermore, it should be understood that HIV transmission is directly dependent on the viral load, its concentration in the infected body fluid, and the susceptibility of the host [31, 32]. It is necessary to emphasize this because HIV cannot survive outside the bloodstream or lymph tissue and is easily inactivated by exposure to common detergents and disinfectants, so understanding the means of transmission is essential to reduce the stigma around people living with HIV (PLWH), mainly among health professionals [33].

Between the initial contamination and severe cases of immunosuppression such as the acquired immunodeficiency syndrome (AIDS), basically, the pathogenesis of HIV infection and the progression between its phases are related between the properties of the virus, risk factors, and the host's immune response. Patient adherence to antiretroviral therapy, that is, the balance between these items, will determine the development of the symptomatic and asymptomatic phase, AIDS, and even the medium- and long-term experience of the host [2, 32–34]. Among the main properties of HIV is the viral replication cycle that can be in the following steps: (1) binding in the cell receptor; (2) cell surface fusion; (3) uncoating; (4) reverse transcription; (5) integration of proviruses; (6) translation; (7) assembly of viral proteins; (8) budding; and (9) release [2, 35, 36].

In summary, HIV replication occurs when the heterodimer proteins gp120 and gp41 of the viral envelope bind to proteins in the cell membrane of target cells; that is, gp120 binds to CD4 monomeric glycoprotein on the cell surface of T lymphocytes or precursor T cells of lymphatic tissues such as bone marrow and thymus, macrophages, eosinophils, dendritic cells, and microglial cells [2, 21, 37–39] and after that, viral RNA is released inside the cells and tissues that will follow its cycle replication from the early stages of infection can be intensely active, as well as allowing the establishment of a latent infection, particularly known as permanent viral reservoirs promoting a major obstacle in the complete eradication of HIV infection and effectiveness in antiretroviral treatment [40–44].

It is estimated that between 10 and 12 days after the initial infection, the levels of viral RNA viremia in the blood plasma will increase slightly providing the anti-HIV

#### *HIV Infection and Oral Manifestations: An Update DOI: http://dx.doi.org/10.5772/intechopen.105894*

antibody seroconversion phase that occurs in a variable period of 3–5 weeks, and this period of the infection is critical, as it indicates that the infected host is transmissible [45–48] and is also possible to detect viral RNA in blood plasma by amplification methods such as reverse transcription polymerase chain reaction (RT-PCR) [49–51]. However, prior to the seroconversion of anti-HIV antibodies, there is a period of time in which the infection is present, but the antibodies are still not detectable; this period is known as the serological window, which, according to the literature, varies from 3 months to a longer period [52–54].

In the acute phase, the CD4+ T cell count decreases dramatically, while the serum levels of viral particles rise proportionally, which is usually of short duration because the host begins to generate humoral and cellular immune responses that partially control viral replication [55, 56]. And as the specific immune response progresses, primarily mediated by cytotoxic CD8+ T cells that produce the initial control of viral replication at this stage of infection, viremia tends to decrease until it reaches stable or undetectable levels signaling the beginning of the chronic phase [57–59]. However, even with this immune response, it is possible to verify the qualitative functional impairment of the immune responses due to HIV, which can be described as a dysfunction of CD4+ T cells and other cells of the immune system, with the need to complement the host's defense lines with antiretroviral therapy [2].

Clinically, PLWH in most cases will present symptoms from a few days to weeks from exposure and contamination by HIV; usually, individuals have systemic symptoms similar to flu or mononucleosis, such as fever, weight loss, night sweats, constant diarrhea, malaise, lymphadenopathy, arthralgia, pharyngitis, and myalgia [60, 61]. These clinical characteristics mentioned above are heterogeneous and may vary between cases; however, something that is common and previously documented is that individuals who delay in starting antiretroviral therapy or maintain inconsistency in treatment and who present the above-mentioned symptoms for a longer duration, which may worsen the infection, leading to systemic and oral opportunistic infections, secondary malignancies, and neurologic manifestations [62, 63].

#### **2. HIV and oral manifestations**

#### **2.1 HIV and oral cavity**

Systemic and local opportunistic infections caused by HIV will directly impact the innate immune response, impact and trigger negative consequences on quality of life, and increase the morbidity of HIV infection; among the main local opportunistic infections, we cite oral lesions (OLs) [64, 65]. OLs are commonly among the first signs and symptoms of HIV infection, and certain lesions, such as necrotizing periodontitis (NP), Kaposi's sarcoma, or linear gingival erythema (LGE), as they are naturally found in PLWH, can serve as a means of diagnosis or indications for individuals with HIV infection status unknown [66–68].

In the past, when the individual was diagnosed with HIV or was undisciplined about antiviral treatment and oral hygiene, the occurrence of certain OLs could predict the progression of chronic infection to acute phases and even AIDS [68, 69]. The presence of OLs in PLWH using antiretroviral therapy (ART) can serve as a marker of viral resistance to medication and, consequently, reduce the effectiveness of ART, indicating the replacement of the current medication. According to Heron and Elahi [70], the prevalence of OL will vary with the use of ART, so specific lesions, such as candidiasis, hairy leukoplakia, and Kaposi's sarcoma, clinically, have shown a lower prevalence in patients who are regular users; however, evidence has shown that lesions, such as oral warts (OWs) and salivary gland diseases, are more prevalent resulting from the use of ART [71].

Oral health care is a vital component for maintaining a satisfactory general state of health and quality of life for PLWH, so it is interesting for health professionals to recognize and reinforce this care of adequate oral hygiene [72, 73], because when there is no such care and due to the immunosuppression conditions and systemic proinflammatory state of HIV-infected individuals and when we associate these systemic conditions with PLWH sites, they are simultaneously more prone to develop moderate and severe OLs such as oral candidiasis (OC), oral hairy leukoplakia (OHL), oral warts, oral aphthous ulcers, and oral herpes even in the presence of ART, demonstrating that the lack of oral hygiene or inadequate hygiene will have a high direct negative impact on the health of this population [74–76].

#### **2.2 HIV and risk of oral transmission**

Since HIV discovery, the means of transmission of HIV has been routinely studied aspects of infection, and until the present day, they are reasons for fear and stigma by the general population and even health professionals such as dentists [33]. Among the most controversial means of transmission is the oral cavity, and the presence of OLs that can serve as facilitators for transmission and contagion has been widely discussed [43]. Although it is known that HIV has periodontal tissues as reservoirs for its latency period, some studies that tried to detect the presence of viral particles in the cells of the oral epithelium demonstrated the absence of HIV in their results, making the transmission through the oral cavity as a somewhat questionable [77].

In theory, HIV infection *via* oral route would occur through oral sex; however, the data indicate low rates of oral HIV transmission. According to the literature studies, when there are cases of serodiscordant partners, the risk of contracting HIV by oral sex is estimated at between 0.04 and 0.06%, which has been shown to be well below the rates of anal sex, which is estimated at around 1.4%, and through sharing sharp instruments, which is estimated at between 0.63 and 2.4% [78–81]. To understand this low prevalence of oral transmission, we first need to understand that the oral epithelium is part of the innate immune system acting as a physical barrier that protects the underlying tissues from infection by pathogenic microorganisms such as HIV; that is, for oral contagion to occur by HIV, there must be a discontinuity in this oral tissue and, beyond this line of defense, the oral cavity [79]. In addition, the oral cavity has saliva and crevicular fluid as a means of defense, due to its low hypotonicity, which can act as antimicrobial factors, as well as macrophages, natural killer cells, and neutrophils, which will play important roles in the immune response of the oral mucosa [43, 70].

Although clinical and statistical data show that the oral transmission of HIV in adults is uncommon, it is understood that OL or mechanical trauma to the tissues of the oral mucosa causing ruptures or damage to the oral epithelium may be risk factors for the oral transmission of HIV, and key populations such as crack users, sex workers, and men who have sex with men may be more likely to be infected due to risky behaviors. As seen above, transmission in adults is rare, but postnatal vertical transmission seems to be a risky means of transmission to neonates, since in cases of HIVinfected postpartum women and neonates who were not contaminated via the uterus, they may contract HIV at ingesting infected vaginal secretions or amniotic fluids during childbirth or even while breastfeeding [82, 83].

#### **2.3 HIV infection and oral mucosal**

As discussed above, oral mucosal infections are commonly seen in HIV-infected individuals, suggesting that HIV infection is a risk factor for pathologies such as periodontal disease (PD), oral candidiasis, oral ulcers (OUs), angular cheilitis, and verrucous lesions [84, 85]. In fact, the literature indicates that ART-naïve PLWH users are more likely to have at least one OL during their lifetime, around 70–90% more likely when compared with PLWH ART users. Interestingly, this relationship may be proportional, because in the case of ART use, the appearance of these oral manifestations is still commonplace, but at a lower incidence, which is due to the fact that OLs, such as periodontitis, have multifactorial etiologies such as the presence of dental biofilm, and in cases of inadequate oral hygiene or absence of it, there will still be risks of oral manifestations [86, 87].

Therefore, it should be understood that the etiology of infections in the oral mucosa of ART-naïve PLWH has an intriguing combination because of systemic immunodeficiency due to the depletion of CD4+ T cells; local factors such as dental biofilm, environmental factors such as smoking, and compromise of oral defense cells producing interleukin-17 (IL-17) may be associated with increased susceptibility to opportunistic oral lesions. However, when ART is present, this incidence rate of OL tends to decrease; studies show that after the prescription and continuous use of ART, oral manifestations such as candidiasis, oral warts, hairy leukoplakia, and angular cheilitis will resolve as the immunosuppression is resolved by increasing the CD4+ T cell count and decreasing the viral load; however, it should be noted that each lesion will take a certain time to resolve due to the different associated causal factors as mentioned above, mainly factors related to impaction in the oral microbiota that undergo changes in the oral bacterial ecosystem [88–90].

#### **2.4 HIV infection and oral microbiome**

In the oral cavity, the role of the oral microbiota is extremely relevant to determine the health or disease of individuals; that is, when there is a process of oral dysbiosis, the diversity and composition of the oral microbiome changes overmuch. In PLWH cases, oral infections are commonly associated with significant proportions of highly pathogenic species such as *Fusobacterium nucleatum*, *Porphyromonas gingivalis*, *Prevotella denticola*,*Tannerella forsythia*, *Prevotella intermedia*,*Treponema denticola*, and *Aggregatibacter actinomycetemcomitans*. In the oral cavity of PLWH, microbial diversity was lower in individuals of this group than in individuals free of HIV infection and patients using ART; that is, in this HIV-infected population, the presence of aggressive bacteria was greater, and moreover, the presence of more virulent fungal communities can be identified. Therefore, the literature suggests that oral dysbiosis in PLWH promote greater chances of OL appearances due to the presence of more aggressive bacterial and fungal communities, even with a lower diversity of strains in the region [91–93].

#### **2.5 Oral lesions caused by HIV infection**

Several studies in the literature show the great harmful impact of HIV infection on the quality of life and oral health of this population [69, 94–104]. According to the Joint United Nations Program on HIV/AIDS (UNAIDS) in 2020, globally, there are about 37.7 million people living with HIV, with 1.5 million newly cases in 2020 alone,

and according to studies, the prevalence of OL in PLWH has a range between 40 and 93%, and this variance will depend on geographic and socioeconomic issues, access to ART and health services, and factors influencing a good quality of life [105]. As seen, OLs are commonly among the first signs and symptoms of a possible HIV infection and can be used as a diagnostic method suggestive of HIV, and these lesions were classified as lesions strongly associated with HIV infection, lesions commonly associated with HIV infection, and lesions seen in HIV infection (**Table 1**) [106, 107]. As for the quality of life of PLWH, OL can be associated with acute pain, chewing and feeding difficulties, esthetic impairment, speech problems, and impaired social life; thus, the need for adequate care, management, and treatment, as well as the prevention of oral diseases, is the duty of health professionals [33].

#### **2.6 Oral lesions and their relationship with CD4 count and viral load**

In addition to their diagnostic importance, OLs are useful to base a prognosis on the stages of infection, as, according to the literature, they will serve as clinical parameters with CD4+ and CD8+ cell counts. Since the introduction of ART, there has been a vertiginous drop in the morbidity and mortality of PLWH, and the lower presence of OLs in HIV-infected patients is also associated with this. That is, the literature indicates that the amount and severity of OL is also directly associated with immunosuppression, so the tendency is to have a high prevalence of OL in patients with a low CD4+ cell count (<200 cells/mm<sup>3</sup> ) and high viral load (>55,000 copies/ mL). In cases of ART-naïve or newly diagnosed individuals, the presence of moderate or severe OL and a CD4+ cell count below 200 cells/mm<sup>3</sup> , it is necessary to start treatment with ART and dental treatment [75, 108–111].

#### **3. Oral lesions clinical characteristics**

#### **3.1 Oral candidiasis**

Oral candidiasis (OC) is among the most common opportunistic infections among PLWH, with an estimated prevalence of between 15% and 80% in adults living with HIV. The OC is a fungal infection caused by the proliferation of different strains such as *Candida albicans*, *Candida tropicalis*, *Candida parapsilosis*, *Candida glabrata*, *Candida krusei*, and *Candida dubliniensis* and is usually associated with low CD4+ cell counts and risk factors such as smoking, being an important marker for the individual's immunity status and among the clinical features of OC we cite [112–120]:




#### **Table 1.**

*EC-clearinghouse oral lesions associated with HIV infection classification.*

• Edema.

Currently, three types of OC are observed: pseudomembranous candidiasis, erythematous candidiasis, and angular cheilitis [112–120].

#### *3.1.1 Pseudomembraneous candidiasis*

They appear as whitish plaques, pasty consistency, can be found on the buccal mucosa, lingual belly, periodontium, hard and soft palate, labial region, and oropharyngeal region. Such plaques are formed by a mixture of fungal hyphae, desquamated epithelium, and proinflammatory cells that, when removed, leave the underlying surface red or bleeding. As for the clinical diagnosis, it is made through clinical symptoms, and the histological diagnosis can be used through the direct smear [112–118].

#### *3.1.2 Erythematous candidiasis*

They appear as petechiae or reddish ecchymoses, commonly associated in the region of the hard palate (indiscriminate use of complete dentures), dorsum of the tongue (similar to areas of depapillation), and buccal mucosa. In most cases, these lesions present characteristic symptoms such as burning mouth and altered taste. As for the clinical diagnosis, it is made through clinical symptoms, and the histological diagnosis can be used through incisional biopsy [112–118].

#### *3.1.3 Angular cheilitis*

It presents as linear fissures or ulcers in the flaky labial commissures, which can be unilateral or bilateral, with a whitish color, sometimes blisters, and are usually associated with small white plaques. In cases of severe immunosuppression or AIDS, angular cheilitis may be related to erythematous candidiasis or pseudomembranous candidiasis. Clinically, the patient reports itching and burning in the labial commissure; the clinical diagnosis is made through clinical symptoms, and the histological diagnosis can be used through incisional biopsy [112–118].

#### *3.1.4 Treatment*

The treatment of OC can be topical and/or systemic, depending on the severity of candidiasis, immunosuppression, and risk factors.

	- a. Clotrimazole (10 mg/g): use three times a day for up to 28 days.
	- a. Nystatin (100,000 IU/ml): use four times a day for 14 days, dosage: 1 to 6 ml of oral suspension.
	- a. Fluconazole (150–200 mg): use once daily for 14 to 42 days.
	- b. Ketoconazole (200 mg): use once daily for up to 14 days.
	- c. Itraconazole (100 mg): use once daily for up to 7 days, dosage: 2 tablets (200 mg) daily.

#### **3.2 Periodontal disease**

Periodontal disease (PD) can be categorized simply as gingivitis and periodontitis; PD is an infectious inflammatory disease of multifactorial etiology [121, 122]. Its main etiology is the interaction among dental biofilm, host immune defense, and risk factors. Therefore, the association among pathological microorganisms, proinflammatory cytokines, oral dysbiosis, and cytotoxic factors causes an intense inflammatory response, which leads to the destruction of periodontal tissues and potentially resulting in tooth and bone loss [123–125].

Host habits, such as poor oral hygiene and smoking, and systemic diseases, such as AIDS, can predispose and worsen the progression of PD, as HIV infection alters the immune system, progressively impairing the immune response, favoring a more

intense PD, such as acute and necrotizing. Necrotizing periodontal disease is the most severe form of PD due to rapid onset, severe pain, severe bone loss, suppuration, ulcerations, and areas of tissue necrosis. Among the clinical features of gingivitis and necrotizing periodontitis, we have the following [126, 127]:


#### *3.2.1 Linear gingival erythema*

Linear gingival erythema (LGE) is characterized by an erythematous band located on the free marginal gingiva; it can be generalized or localized and usually does not show signs of inflammation due to bacterial plaque accumulation. In other words, LGE can be considered a chronic non-plaque-induced gingivitis, a precursor of necrotizing diseases (**Figure 1**).

LGE is among the main oral signs and symptoms of HIV infection and possibly occurs due to the dysbiosis of the gingival sulcus microbiota and systemic immunosuppression. As a form of differential diagnosis between a common chronic gingivitis and LGE, in addition to the low presence and biofilm, the negative response to scaling and root planning treatment can be fundamental for the diagnosis [112–114, 128].

#### *3.2.2 Necrotizing gingivitis*

Necrotizing gingivitis (NG), also known as Vincent's disease or trench mouth, is the most severe form of PD and tends to be present in individuals with severe immunosuppression; it is characterized by rapid onset, ulcerations, tissue necrosis,

*HIV Infection and Oral Manifestations: An Update DOI: http://dx.doi.org/10.5772/intechopen.105894*

**Figure 1.** *Clinical linear gingival erythema.*

**Figure 2.** *Clinical necrotizing gingivitis.*

suppuration, bleeding, foul odor, severe pain, and loss of interdental papillae (**Figure 2**) [127].

#### *3.2.3 Necrotizing periodontitis*

Necrotizing periodontitis (NP) is the natural evolution of NG; it is characterized by loss of soft tissue as a direct result of necrosis and acute ulceration arising from NG and presents a rapid bone destruction and extensive loss of the clinical level of bone attachment that can be generalized or located (**Figure 3**) [127].

**Figure 3.** *Clinical necrotizing periodontitis.*

#### *3.2.4 Treatment*

The treatment of periodontal diseases boils down to topical and systemic chemicalmechanical therapy [127].

	- a. Chlorhexidine digluconate (0.12%: use two to three times a day for 10–14 days, dosage: 3 mL of oral solution.
	- a. Amoxicillin (500 mg): use three times a day for 7 days.
	- b. Metronidazole (250 mg): use twice daily for up to 10 days.
	- c. Amoxicillin and metronidazole can be combined to broaden the spectrum of action of antibiotic therapy.

#### **3.3 Oral hairy leukoplakia: (OHL)**

Oral hairy leukoplakia (OHL) is also among the most common oral signs and symptoms of HIV infection; it is usually caused by Epstein-Barr virus infections and is white asymptomatic plaques with a corrugated surface or a velvety hair-like appearance, which can be found on the lateral borders, unilaterally or bilaterally, of the tongue and in more severe cases also found on the dorsum or belly of the tongue, on the floor of the mouth, and on the buccal mucosa. If there is no removal of the plaque, the suggestive diagnosis is OHL, and if it comes out, it will be candidiasis. Among the histological features of OHL, we evidenced areas of hyperkeratosis, parakeratosis, acanthosis, papillomatosis, and the presence of layers of ballooned cells similar to koilocytes with nuclear alterations in the spinous layer, epithelial inflammatory infiltrate, and connective tissue [112–114, 129–132].

#### *3.3.1 Treatment*

The treatment of OHL is not just periodontal, and necrotizing diseases boils down to topical and systemic chemical-mechanical therapy [129–132].

	- Podophyllin (25%): use three times a day for 7–14 days, use by applying the oral solution locally.
	- Prevention of smoking and alcoholism.
	- Acyclovir (800 mg): use five times daily for 7–14 days.
	- Desciclovir (250 mg): use three times daily for 7–14 days.
	- Valacyclovir (1000 mg): use three times daily for 7–14 days.
	- Surgical excision of the lesion with an electric scalpel or laser.

#### **3.4 Kaposi's sarcoma**

Kaposi's sarcoma is a neoplasm commonly associated with individuals with AIDS; its etiology is usually linked to the oncovirus human herpes virus-8 (HHV-8) and originates from endothelial cells as a direct response to HHV-8 infection and immunosuppression caused by HIV. Clinically, the lesions are found in the form of asymptomatic macules or nodules, fast growing, reddish, bluish, or purple, and in some cases, in addition to the OL, lesions in the gastrointestinal and pulmonary tracts can be found. They are usually located in the palate or alveolar process and can lead to bone destruction, tooth mobility, and invariably tooth loss. Histologically, this neoplasm presents fusiform tumor cells, similar to smooth muscle, fibroblasts, and myofibroblasts [108, 112–114].

#### *3.4.1 Treatment*

The treatment of Kaposi's sarcoma consists of excisional biopsy, radiation therapy, or chemotherapy [108, 112–114].

#### **3.5 Non-Hodgkin's lymphoma (NHL)**

Non-Hodgkin's lymphoma (NHL) is the most uncommon OL associated with HIV infection; however, apart from Kaposi's sarcoma, it is the second most common malignancy among PLWH, with an average prevalence of 4%. NHL is a type of malignant neoplasm of origin in the cells of the lymphatic system and with an unordered diffusion and clinically appears as lymphadenopathy of the head and neck, armpits, and/or groin; among the most common signs and symptoms, the individual has nocturnal sweating, pyrexia or hyperpyrexia, itching, weight loss, and rapidly growing oral nodules in the alveolar process and tongue [112–114, 133–135].

#### *3.5.1 Treatment*

The treatment of NHL is based on excisional biopsy or puncture and with confirmation the individual should start with immunotherapy, radiotherapy, or chemotherapy [112–114, 133–135].

#### **3.6 Oral ulcers**

Oral ulcers (OUs) are erosive lesions that occur in the oral epithelium, and when the epithelium sloughs, the nerve endings of the oral epithelium will be exposed and trigger symptoms such as pain provoked and exudate, causing difficulty in swallowing and impaired speech and chewing. They can appear in all the areas of the oral mucosa, and among PLWH, it has a prevalence of about 50%; OUs can be classified into minor aphthous ulcers and major aphthous ulcers [112–114].

#### *3.6.1 Minor aphthous ulcers*

They are minor ulcerative lesions with about 2–5 mm in diameter and occur on nonkeratinized mucosa, have a predilection for areas of the buccal mucosa and lips, are clinically more superficial, covered by a whitish pseudomembrane, surrounded by an erythematous halo, and are extremely painful [112–114].

#### *3.6.2 Major aphthous ulcers*

They are larger ulcerative lesions measuring over 1 cm in diameter and can occur in both keratinized and nonkeratinized areas, generally affecting the lateral border of the tongue, soft palate, floor of the mouth, buccal mucosa, oropharynx, and alveolar process. Clinically, they have a crater-like appearance with raised edges and covered by a yellowish-white pseudomembrane and may be accompanied by regional lymphadenopathy [112–114].

#### *3.6.3 Treatment*

The treatment of OU is summarized in a topical therapy, in which the individual must maintain good oral hygiene, use 0.12% chlorhexidine digluconate mouthwash or dexamethasone mouthwash (0.5 mg/5 cc), rinse for 5 minutes before spitting, and use three to four times a day for up to 10 days. The use of topical ointments, such as triamcinolone acetonide, can be applied under the ulcer area two to three times daily for up to 7 days [112–114].

#### **3.7 Salivary gland diseases**

The enlargement of the major salivary glands affects the parotid, sublingual, and submandibular glands; clinically, xerostomia, unilateral or bilateral, and asymptomatic edema, in addition to esthetic embarrassment and social stigma, are observed. Histologically, the presence of focal sialoadenitis with an infiltrate of proinflammatory cells and CD8+ T lymphocytes can be observed [112–114].

#### *3.7.1 Treatment*

A specific treatment for the enlargement of the major salivary glands does not exist; to treat symptoms such as xerostomia, the use of artificial saliva or the habit of chewing gum to increase salivary volume is recommended, and some studies have shown that radiotherapy may be a viable treatment to reduce the size of the glands [112–114].

#### **3.8 Melanotic hyperpigmentation**

Oral melanotic hyperpigmentation is another common lesion in PLWH, and once the differential diagnosis of ethnic melanic pigmentation is removed, it can be

indicated that, once present in the oral cavity, it is a possible factor of HIV infection. Clinically, there is a black, brownish, or brown spot or macula, typically asymptomatic and may occur due to increased release and dysregulation of alpha melanocytes caused by certain types of ART, such as zidovudine and antifungal drugs, especially to treat and *Mycobacterium avium* intracellulare [112–114].

#### **3.9 Human papillomavirus**

Human papillomavirus (HPV) can infect the oral mucosa, resulting in the development of oral verrucous lesions. Oral warts (OWs) usually present nodular or pedunculated lesions with a sessile base, with a firm consistency; they can be solitary or multiple lesions, white or pink in color, and can have smooth or irregular surfaces, similar to a cauliflower. The OWs caused by HPV are among the most prevalent lesions of PLWH with a reported prevalence of about 0.5–6.9%, and HPV can be classified into subtypes according to its oncogenic level, and in the oral cavity, subtypes 6 and 11 are the most prevalent; about 90%, in OWs such as condylomas and laryngeal papillomas, have lower oncogenic potential. HPV is highly sexually transmitted; being frequent in the genital and anal region, its incidence in the oral mucosa is due to acts of self-inoculation or oral sexual contact [112–114, 136–139].

#### *3.9.1 Treatment*

The basic treatment of OW is summarized in the excisional biopsy of the nodule, either by removal with a surgical laser or by electric scalpel or cryosurgery. Topically, a cream called imiquimod (50 mg/g) serves as an immunomodulatory cream that must be applied to the wart site once a day, three times a week for up to 28 days. Systemically, the use of antivirals such as cidofovir (5 mg/kg) is recommended, which should be administered once a week for up to 14 days [112–114, 136–139].

#### **4. Conclusion**

Host's immune, oral hygiene, and HIV infection course could be considered a directly key determinant for oral mucosal infection linked to HIV. Therefore, to understand the immunological key elements in the oral health of PLWH is essential to alerted healthcare workers regarding HIV infection severity, because compromised oral barrier integrity will facilitate HIV infection, oral dysbiosis, microbial translocation along different types of mucosal tissue, and the spread of microorganism products into the oral epithelial tissue, which may predispose to opportunistic infections and systemic inflammation, such as various oral lesions and neoplasms. This chapter presented various studies and discussed the newly knowledge about HIV infection and its importance to oral mucosa infections, so this review might be helpful to the diagnosis and treatment of various oral lesions in PLWH.

#### **Acknowledgements**

The authors would like to acknowledge the help from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Ministry of Education - Brazil– Grant code 001. LFAM is a CNPq Grantee (#314209/2021-2). Publication of the article was supported by Public Notice PAPQ, PROPESP/FADESP of the Federal University of Pará.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Appendices and nomenclature**

Human Immunodeficiency Virus (HIV); HIV-type 1 (HIV-1); HIV-type 2 (HIV-2); People Living with HIV (PLWH); Acquired Immunodeficiency Syndrome (AIDS); Reverse Transcription Polymerase Chain Reaction (RT-PCR); Oral lesions (OL); Antiretroviral therapy (ART); Joint United Nations Programme on HIV/AIDS (UNAIDS); Oral candidiasis (OC); Periodontal disease (PD); Linear gingival erythema (LEG); Necrotizing gingivitis (NG); Necrotizing periodontitis (NP); Oral hairy leukoplakia (OHL); Human Herpes Virus-8 (HHV-8); Non-Hodgkin's lymphoma (NHL); Human papillomavirus (HPV); Oral warts (OW).

### **Author details**

Ricardo Roberto de Souza Fonseca1,2\*, Rogério Valois Laurentino1,2, Luiz Fernando Almeida Machado1,2, Carlos Eduardo Vieira da Silva Gomes3 , Tatiany Oliveira de Alencar Menezes3 , Oscar Faciola Pessoa<sup>3</sup> , Aldemir Branco Oliveira-Filho<sup>4</sup> , Tábata Resque Beckmann Carvalho<sup>5</sup> , Paula Gabriela Faciola Pessoa de Oliveira<sup>5</sup> , Erich Brito Tanaka<sup>5</sup> , Jorge Sá Elias Nogueira<sup>5</sup> , Douglas Magno Guimarães<sup>5</sup> , Marcelo Newton Carneiro<sup>5</sup> , Paula Mendes Acatauassú Carneiro<sup>5</sup> , Aluísio Ferreira Celestino Junior<sup>5</sup> , Patricia de Almeida Rodrigues<sup>5</sup> and Silvio Augusto Fernandes de Menezes<sup>5</sup>

1 Biology of Infectious and Parasitic Agents Post-Graduate Program, Federal University of Pará, Belém, Brazil

2 Virology Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Brazil

3 Dentistry Post-Graduate Program, School of Dentistry, Federal University of Pará, Belém, Brazil

4 Study of Research Group on Vulnerable Populations, Institute of Coastal Studies, Bragança, Brazil

5 School of Dentistry, University Center of State of Pará, Belém, Brazil

\*Address all correspondence to: ricardofonseca285@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 9**

### Psychiatric Problems in HIV Care

*Seggane Musisi and Noeline Nakasujja*

#### **Abstract**

Psychiatric problems associated with HIV/AIDS are many, varied and often bidirectional and they are often neglected. Their presence compromises HIV care and prevention efforts. Unaddressed, they compromise treatment outcomes, increase HIV virus–resistant strains, leave pockets of potential HIV spread in the community and lead to poor quality of life and early death of Persons Living With HIV/AIDS. This chapter focuses on specific HIV-associated mental disorders and their management. However, the mental health problems of HIV/AIDS go beyond disorders to include social, family and community problems such as the problems faced by AIDS orphans, widowhood, family disruptions, multiple deaths, bereavements, poverty, stigma, caregiver burden, education and occupational difficulties etc. All these need to be addressed in holistic HIV care. This calls for more research and integration of mental healthcare in all HIV/AIDS treatment and prevention programs.

**Keywords:** HIV/AIDS, anxiety, depression, mania, psychosis, dementia

#### **1. Introduction**

HIV/AIDS is an intimately sexually embedded disease and as such connected to human reproduction and hence human perpetuation [1]. Sexuality, itself, is a biopsycho-social phenomenon, the regulation of which has fascinated humans from time immemorial. It is a subject of religious, cultural and ultimately government concern especially as it impacts human health and hence healthcare provision. Secondly, HIV/AIDS is a fatal condition and mainly a disease of those in the reproductive age. However, it now spans all ages as it can be transmitted perinatally from mother to fetus and, can be managed with modern drugs up to old age. This makes HIV/AIDS a chronic disease for which one has to adjust and take medications for life hence inherently laden with problems associated with medication compliance and adherence. Being predominantly sexually transmitted and fatal makes HIV/AIDS highly stigmatized. HIV is an infectious disease which is predominantly sexually transmitted [2]. Prevention of HIV infection is a prolog of public health, but in the domain of human behavioral change, calling for measures to regulate human behavior to curb HIV infection risk. Thus, mental health problems impacting HIV infection risk become of utmost concern in HIV care [3]. The HIV virus is neuropathic invading brain tissue soon after infection and giving rise to a host of psychiatric disorders which call for treatment [2]. The secondary infections associated with HIV/AIDS and the drugs to treat them as well as the antiretroviral (ARVs) drugs themselves may also cause psychiatric complications [1]. Lastly, the high numbers of HIV/AIDS deaths

have caused much family disruptions due to the orphans left behind as well as widowhood with significant socio-economic, educational and occupational ramifications [4–6]. For all these reasons and many more as will be seen, the psychiatric, social and behavioral mental health problems associated with HIV/AIDS are many and call for their management in HIV care [5–7]. This chapter will give an overview of the mental health problems which are frequently encountered in HIV care, their effects and how to manage them. It will also discuss the need to integrate mental health care in HIV/ AIDS management and how this impacts outcomes of treatment.

#### **1.1 Classification of the mental health problems encountered in HIV care**

Significant research has shown that the relationship between mental illness and HIV/AIDS is bidirectional. First, mental illness and other premorbid psycho-behavioral patterns are risk factors to contracting HIV infection [2, 5, 7]. On the other hand HIV/AIDS predisposes to getting psychiatric disorder. Both have to be addressed in HIV care efforts and infection spread prevention. Unaddressed, they leave pockets in the population which hinder effective control of the HIV pandemic.

### **2. Premorbid behavioral psychopathology in HIV/AIDS**

In HIV-related mental health problems and illness, it is important to discuss premorbid psychopathology and psychosocial risk behaviors in HIV/AIDS as these factors complicate the post-infection clinical picture and impact treatment outcomes including treatment adherence and HIV infection risk [5]. Premorbid behavioral psychopathology in HIV/AIDS includes the following:

	- a.Orphans and other vulnerable children (OVCs)
	- b.Marginalized poor communities
	- c.Conflict communities—Refugees, Displaced Persons, war & disaster affected
	- d.The elderly
	- e.Women

Personality disorders represent enduring maladaptive ways of behaving and coping with life's challenges often with non-conformity to society's expectations, adjusting to stresses, or relating to others [8]. Examples include Antisocial Personality

#### *Psychiatric Problems in HIV Care DOI: http://dx.doi.org/10.5772/intechopen.106077*

Disorder, Borderline Personality Disorder, Dependent Personality Disorder or Avoidant Personality Disorder. Individuals with Personality disorders are more likely to not comply with treatment recommendations, to break rules, to abuse substances, not to practice safe sex and to present as difficult patients including being manipulative, dependent or avoidant. They present problems of treatment non-compliance and high HIV-infection risk behaviors. Management consists of long-term psychotherapy geared to behavior change, setting boundaries and instituting firm limitations.

In Western countries, high HIV-infection risk groups were classified as Homosexual men, Hemophiliacs, Intravenous drug users (Heroin) and Blacks (Haitians) [5]. In Africa, HIV-transmission is by and large heterosexual followed by mother-to-child (vertical) transmission [5]. The determinants to HIV infection here are related to socio-economic and power dynamics [2]. Thus high rates of HIV have been found in post-conflict communities, fishing villages and overcrowded urban centers with high rates of poverty and loosely connected family ties such as slums, casual workers, recreation and bar attenders [5, 7]. Mother-to-child transmission remains a big problem because of the unbalanced power dynamics in matters pertaining to negotiating sex and money which makes women more subordinate and thus more susceptible to HIV infection. These social determinants also operate for the common mental disorders of depression, anxiety, post-traumatic disorder associated with family violence and substance abuse.

Individuals with pre-existing Severe Mental Illness (SMI), such as Schizophrenia, Bipolar Disorder and Major Depression, have been found to have a higher prevalence of HIV infection compared to those without SMI [9, 10] . In a study of SMI patients at a psychiatric hospital in Uganda, Maling et al. [9] found a prevalence of HIV infection of 18% compared to 7% in the general population. Lundberg et al. [10] found an HIV prevalence of 11.3% in hospitalized SMI patients. Thus SMI predisposes to HIV infection risk. Lastly, Nakimuli et al. [11, 12] found a high prevalence of HIV-infection in individuals with alcohol dependence and depression in Uganda. These groups of individuals with pre-existing mental disorders are usually less likely to be compliant with ARV medication adherence and they are also less likely to practice safe sex such as condom use [13]. Moreover, often HIV prevention efforts have not targeted the population of the mentally ill for their messaging thus leaving a pocket of potential HIV infection spread in the community. Management calls for definitive treatment of the SMI with appropriate psychotropic medications and psychotherapy and follow up as these conditions tend to be life-long [14]. All this points to the need to integrate mental healthcare in efforts of HIV care and prevention.

Vulnerable populations comprise of those groups of people or communities within a country that have characteristics putting them at risk of being excluded from social, economic, political or environmental resources hence needing humanitarian assistance due to the barriers they face [15]. In HIV/AIDS care, these groups often comprise of, but are not limited to, orphans and other vulnerable children (OVCs), marginalized poor communities,, the elderly, and conflict/post-conflict communities including refugees, immigrants and displaced persons, as well as the war and disaster affected. These groups tend to have poor access to health services and have higher rates of mental illness, especially depression and Post-traumatic Stress disorder and are at increased risk of HIV-infection [16]. They are also less likely to be targeted in HIV care and prevention messaging. Specific measures need to be taken to ensure their access to psychosocial care. Group Support Psychotherapy (GSP) has been found to be especially effective in addressing their care needs [16, 17].

#### **3. Acute psychological problems and reactions following the HIV/AIDS diagnosis**

Despite effective pharmacotherapies in HIV care, a positive HIV test still invokes stressful psychological reactions, which are not the result of HIV neuronal involvement [5]. The reasons for these reactions are many including the following:


The observed psychological reactions do not connote brain pathology but a psychological, emotional and behavioral reaction to the news that indeed one is now infected with HIV hence challenging the individual's ego defense and coping mechanisms. The frequently encountered psychological reactions to the HIV diagnosis include Adjustment Disorders, Acute Stress Disorder, Post-traumatic Stress Disorder and Suicidal ideations [5]. They occur early on learning of the diagnosis and often present as psychiatric emergences demanding immediate intervention e.g. suicidal attempts, panic attacks etc.

#### **3.1 Adjustment disorders**

News of a positive HIV-infection diagnosis is traumatic and the recipient has to adjust to the new reality. Adjustment disorders occur as emotional or behavioral symptoms occurring within 3 months following the psychologically traumatic stressor of the HIV-positive news causing clinically significant marked distress and causing impairment in social, occupational, academic or other performance [8]. Adjustment disorders occur within 3 months of the diagnosis and do not persist for longer than 6 months. They may take any of the following six forms [8]:


#### **3.2 Acute stress disorder and post-traumatic stress disorder (PTSD)**

Acute Stress Disorder (ASD) has also called Acute Stress Reaction is a transient mental disorder that develops following the traumatic mental stressor, e.g. news of HIV diagnosis [8]. Individual vulnerability and coping capacity play a role in the occurrence and severity of the ASD. The symptoms appear within minutes to 30 days of the impact of the stressful traumatic news of the HIV diagnosis but may disappear within 30 days. If the symptoms persist longer than this, the diagnosis is then changed to Post-traumatic Stress Disorder, PTSD, otherwise the DSM-5 diagnostic criteria for ASD and PTSD are similar and they include [8]:

	- 1.*ASD*: The symptoms occur within 30 days of the trauma (of the HIV diagnosis)
	- 2.*Acute PTSD*: The duration of PTSD symptoms is 30 to 90 days.
	- 3.*Chronic PTSD*: The duration of PTSD symptoms is 90 or more days.
	- 4.*Delayed Onset PTSD*: The PTSD symptoms occur within 6 months or more of the trauma (of the HIV diagnosis).

The risk factors for developing the acute psychological disorders to the HIV diagnosis include [5, 7]:


The management of the acute psychological reactions includes [5]:


#### **4. The specific HIV-associated mental disorders**

These are classified as [5, 7]:


#### **4.1 Anxiety disorders**

Anxiety is defined as an emotional response of excessive fear to a real, imagined or perceived threat or anticipation of a future threat. Affected individuals may experience one or more anxiety states comprising of physiological activation, increased behavioral response, restlessness and cognitive dissonance [8]. Anxiety disorders differ from normative anxiety by being excessive, persistent, typically lasting 6 months or more, and causing impairment in one's life functioning [8]. The prevalence of Anxiety disorders in the general population is about 18% [18] but is higher occurring in about 20–35% of individuals with HIV/AIDS and may evolve from Adjustment Disorders or occur on their own [5, 7, 19]. They take the form of generalized anxiety, panic attacks or obsessional fears. The affected individuals have difficulty controlling apprehension and worry coupled with increased muscular tension, and autonomic hyper-arousal resulting in fear symptoms which include shaking or tremulousness, choking feelings, hyperventilation, increased heart rate, sweating, goose flesh, sleeplessness, increased urinary frequency and gastrointestinal upset with frequent loose stools or even frank diarrhea [8]. Cognitively, one becomes restless, hyper-vigilant, irritable, tense and has difficulty in concentration accompanied by fears of dying, loss of control or something dreadful happening


#### **Table 1.**

*Symptoms and prevalence of anxiety disorders found in HIV/AIDS.*

to them. Some patients develop hypochondriacally fixated with excessive concerns about bodily functions and exaggerating any bodily discomforts or pains. The specific DSM-5 Anxiety disorders found in HIV/AIDS are Generalized Anxiety Disorder (GAD), Panic Disorder, Social Anxiety Disorder, Agoraphobia and Specific phobias [8]. Brandt et al. [19] summarized their symptom characteristics and prevalence as indicated in **Table 1**.

Symptomatic anxiety is arguably the most prevalent psychiatric disorder in HIV/AIDS. It may occur as Adjustment disorder with Anxious Mood, be persistent as GAD and panic attacks, arise sporadically with reminders of the HIV infection (e.g. news of HIV/AIDS deaths, development of new symptoms such as TB or skin changes including Herpes Zoster rashes etc.) or become a chronic condition with preoccupation with physical symptoms or with illness progression. Anxiety Disorders in HIV/AIDS must be treated as they often impair daily functioning interfering with Quality of Life. Psychotherapy with Supportive Counseling and Behavioral Activation techniques should be tried first. Long-term psychotherapy is often useful individually or in groups employing Interpersonal Psychotherapy, IPT [20]; Interpersonal Group Psychotherapy, IGPT [21]; Group Support Psychotherapy, GSP [16]; or Cognitive Behavioral Psychotherapy, CBT [22]. Psychopharmacotherapy is indicated when symptoms persist, are debilitating or present as panic emergences with patients running to hospitals or clinics repeatedly [23]. Short acting benzodiazepines such as Alprazolam or Lorazepam are useful in controlling the acute symptoms of panic attacks. The persistent tension and sleeplessness can be controlled using longer acting benzodiazepines such as Clonazepam. Use of benzodiazepines should be brief, not lasting more than 2 to 3 weeks to avoid dependence to these medications. Antidepressants are indicated for persistent or recurrent symptoms or when depression sets in. The antidepressants of choice include tricyclic antidepressants (imipramine or amitriptyline), SSRIs (fluoxetine, paroxetine, sertraline) or SNRIs such as venlafaxine. These antidepressants must be given in clinically therapeutic dosages and for sufficient duration of at least 6-months, but may stretch to 1–2 years in some patients. Concomitant use of nonprescription medications and substance abuse (alcohol and or illicit drugs) must be looked out for and addressed.

#### **4.2 Mood disorders**

Mood disorders of major concern in HIV/AIDS comprise of Depression and Bipolar Affective Disorder. HIV-associated mood disorders must be distinguished from Primary mood disorders. However, it is important to effectively treat and, if possible, prevent Primary Affective Disorders as these are risk factors for HIV infection as composite SMIs. If not properly addressed, both HIV-associated mood disorders and Primary mood disorders compromise HIV/AIDS care outcomes, increase risk of HIV infection spread and impact the Quality of Life of individuals living with HIV/AIDS.

#### *4.2.1 Depression*

Depression is common in people living with HIV/AIDS (PLWH) with a lifetime prevalence of about 40% [24] compared to 4–8% in the general population [25] and also about 41% of HIV-affected children and adolescents [26]. DSM-5 gives diagnostic criteria for depression as comprising of two or more weeks of depressed mood most of the day, nearly every day and/or diminished interest/pleasure in activities previously enjoyed [8]. These two are accompanied by at least 4 of the following: loss of appetite and weight, sleep disturbance (usually poor sleep), psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness and/or hopelessness, poor concentration and memory, indecisiveness, suicidal ideation or attempts or pre-occupation with death. These depressive symptoms cause clinically significant distress and impairment of functioning and must not be due to effects of substances, other medical conditions or bereavement. Akena et al. [27] described the clinical and associated features of HIV- associated depression in adults as distinct from Depression in HIV-negative individuals. They found that the Depression of HIV/AIDS tended to occur earlier on in the HIV disease (WHO stages I & II) and was not associated with increased immunosuppression (as measured with CD4 counts) but was associated with cognitive decline as measured by the Mini Mental Status Examination, MMSE. Its onset was in older patients, (>30 years), who were more likely to be widowed or never married and had a negative a family history of affective disorder compared to HIV-negative depressed patients. On the Beck Depression Inventory, BDI, depressed PLWH were more likely to have more loss of appetite and weight, had poorer sleep, felt more fatigue, and were more self-critical and indecisive. Studies of Depression in HIV/AIDS have found poorer treatment outcomes and a poorer quality of life in untreated depressive PLWH [28]. They have poorer adherence to treatment recommendations including poor adherence to ARVs [29, 30] and are more likely to engage in risky sexual behaviors including non-condom use [31] and substance abuse [11] as well as domestic violence, child abuse and suicide [5].

Treatment of depression in PLWH includes Social treatments, Psychotherapy and antidepressant medications [30]. Antidepressant medications are almost always indicated in the management of HIV-associated depression because of the biological nature of its etiology being linked to early CNS HIV viral involvement [5]. Commonly used antidepressants include tricyclic antidepressants—imipramine, amitriptyline or their breakdown products of desipramine and nortriptyline respectively; and the SSRI group of antidepressants as quite effective and associated with fewer side effects [32]. These medications include fluoxetine, sertraline, citalopram, escitalopram, paroxetine as well as other types of antidepressants including SNRIs like Venlafaxine. Individual and group psychotherapy has been found to be effective and should always

be combined with the pharmacotherapy. Of particular effectiveness has been IPT and IGPT [20, 21]. More recently GSP as developed by Nakimuli et al. [17] has been found to be especially effective in LMIC in Africa as it addresses commonly associated family and social issues such as stigma, poverty, neighborhood wrangles, poor community welfare including insecurity, water and food shortages in especially post-conflict communities where PTSD, substance abuse and domestic as well as other violence is also common.

#### *4.2.2 Bipolar affective disorder*

Bipolar affective disorder frequently occurs in HIV/AIDS with a prevalence of up to 4.3% compared to 1% in the general population [33]. The DSM-5 diagnostic criteria for Bipolar Affective Disorder, Manic Phase, include at least 1 week of a distinctively elevated, expansive or irritable mood with persistently increased goal-directed activity or energy present most of the day, nearly every day and calling for a need for intervention [8]. This is then accompanied with at least 4 of the following symptoms: inflated self-esteem or grandiosity, decreased need for sleep, increased talkativeness, racing thoughts with flight of ideas, distractibility, over-activity including risky behaviors such buying sprees, high libido with sexual indiscretions, unrealistic business deals, argumentativeness with sometimes aggressiveness and violence. In one study, Nakimuli et al. [34] described the clinical features of HIV-associated secondary mania as distinct compared to Primary Bipolar mania. HIV-related secondary mania is characterized by older age of onset, higher prevalence in females, more likely to occur in widowed, separated or divorced PLWH. Symptomatically, it has more manic symptoms as measured on the Young Mania Rating Scale (YMRS), has more irritable/ elated mood, is more aggressive and disruptive with more decreased need for sleep, paranoid delusions, visual and auditory hallucinations and showing more cognitive impairment on the Mini Mental Status Examination (MMSE). The causes of secondary mania of HIV/AIDS include HIV being the sole organic brain insult to the brain as the virus invades the brain early on, HIV-related opportunistic infections, medication-induced mania e.g. psychotropic medications such as antidepressants, steroids, or even ARVs themselves such as zidovudine or didanosine [5]. An individual with a primary bipolar affective disorder can also be infected with HIV, in which case the Bipolar disorder is considered as comorbid with of HIV/AIDS.

A manic episode in PLWH is disruptive of care and leads to poor treatment compliance, non-adherence to ARVs, risky and unsafe sex as well as substance abuse [7, 35]. Untreated, bipolar affective disorder is associated with job losses, marital breakups and poor quality of life. There is also an increased risk of suicide in Bipolar Affective Disorders compared to the general population. The treatment of HIV-related mania follows the same principles as primary mania [36]. Often, a manic episode demands hospitalization including involuntary commitment and or use of restraints or isolation on a secure ward due to the presenting aggression, violence or its disruptive nature. It is important to achieve quick control of the disruptive manic symptoms as they pause a psychiatric emergence with possible harm to others or property. Quick acting parenteral antipsychotics and benzodiazepines are administered and the patient is placed in a quiet isolated room, secure ward or psychiatric intensive care unit. Rapid neuroleptization using intramuscular injections of Haloperidol Hcl or zuclopenthixol acetate combined with injectable promethazine or lorazepam achieve quick control of the patient's symptoms with the required sedation. These are followed by regular 8 or 12 hourly oral doses of atypical

#### *Psychiatric Problems in HIV Care DOI: http://dx.doi.org/10.5772/intechopen.106077*

antipsychotics such as olanzapine, quetiapine, ziprasidone or risperidone and a longer acting benzodiazepine such as Clonazepam at bedtime for about 1–2 weeks. These are then be tapered down as the symptoms become controlled and mood stabilizers are added to the regimen, such as Lithium Carbonate or anticonvulsants such as sodium valproate, carbamazepine or lamotrigine. Blood levels of these drugs must be checked after 2 weeks of equilibration, to avoid toxicity and maintain therapeutic levels. When all symptoms are controlled medications are tapered down to minimal maintenance doses, to avoid relapses and preferably administered at bedtime only. Bipolar disorders in HIV/AIDS respond very quickly to medications but it needs maintenance therapy to avoid relapses which may become more frequent with cognitive decline. Psychotherapy is commenced as more of a supportive and psycho-educative nature initially and should involve the family as a trialogue involving the patient, supporting family caretaker and the clinician. Family Psychosocial Involvement Interventions have been found to be effective in SMI including Bipolar Affective Disorders [36].

#### **4.3 Psychotic disorders**

Similar to mood disorders in PLWH, psychotic disorders can be either primary predating HIV infection and considered as comorbid to HIV/AIDS or as secondary to HIV infection as new onset psychotic illnesses associated with the HIV/AIDS disease [7, 33, 37]. Severe mental illness (SMI), a category to which psychotic disorders belong, has been associated with high rates of HIV-infection [9, 10]. In a study of individuals with first episode psychosis in Uganda, Maling et al. [9] found an HIV infection prevalence of 18.3% in patients with newly onset psychosis in a psychiatric hospital in Uganda. Lundberg et al. [10] found 11.3% of persons hospitalized with SMI in Uganda to have a HIV infection which prevalence was greater in women. The prevalence of psychosis in PLWH has been reported to be in range of 5–15% [37] . Psychotic disorder is characterized by the presence of delusions, hallucinations, disordered thinking, speech and behavior as well as deterioration in social, occupational and daily functioning due to distorted reality testing [8]. The mechanism of causation of new onset psychotic disorders in HIV/AIDS is complex and multifactorial. Viral invasion of the brain, opportunistic infections and the multiple medications used as well as general debilitation and progression of the disease with cognitive impairment all contribute to causing new onset psychosis of HIV/AIDS [5, 37]. The HIV virus invades sub-cortical structures of the brain including the limbic system. The presence of psychosis in PLWH heralds poor prognosis as untreated or poorly treated psychosis compromises treatment adherence with non-attendance of follow ups and a consequent poor quality of life as well as high HIV infection risk sexual behavior. Early death is common.

The clinical presentation of new onset HIV-related psychosis includes late onset psychosis (>30 years), presence of auditory, visual and tactile hallucinations, paranoid and bizarre delusions, affective symptoms, cognitive impairment and behavioral disturbances [5, 37]. HIV associated psychosis is more common in the late stages of the diseases, especially in untreated or poorly treated PLWH. The symptoms are often of a mixed bag and not well formed unlike those of the classical SMIs. There is usually a negative family history of mental illness.

Management of HIV-related psychosis follows the same principles as the non-HIV related psychoses but with concomitant treatment of the HIV/AIDS itself using ARVs and any associated opportunistic infections [5, 37]. Antipsychotic medications are always indicated and are quite effective, starting with small doses and watching out for side effects which are then also treated. The medications include the typical antipsychotics like haloperidol, trifluoperazine, flupenthixol, fluphenazine or with atypical antipsychotics which usually have less extrapyramidal side effects but more metabolic dyslipidemias. The atypical antipsychotics include Olanzapine, Risperidone, Quetiapine, Ziprasidone, Aripiprazole etc. Often PLWH who have psychosis have poor medication compliance, in which case long acting depot preparations are useful such as monthly Risperidone Consta, Abilify Maintena (Depot Aripirazole), Haloperidol Decanoate, Fluphenazine decanoate, Flupenthixol decanoate or even three monthly depot preparations such as Paliperidone Palmitate. Extrapyramidal side effects are managed with anticholinergic medications such as benzhexhol, benztropine or procyclidine. Unlike classical SMIs, new onset HIVrelated psychoses respond quickly to medications and which may then be tapered off after 3–6 months of effective treatment. However, in some cases long-term maintenance treatment with low antipsychotic doses is necessary. Psychotherapy of a supportive and psycho-educative nature must always be added to the pharmacotherapy and should involve the family as a trialogue involving the patient, supporting family caretaker and the clinician as Family Psychosocial Involvement Intervention [38].

#### **4.4 HIV-associated neurocognitive disorders (HAND)**

HIV-associated cognitive disorder has had considerable research attention in the past 20 years, especially HIV-associated dementia [39]. Neurocognitive disorders or dementias are characterized by difficulties in *attention* (sustenance, selectiveness & processing), *executive function* (planning, habits, decision making, responses, flexibility & error correction), *learning* (memory—immediate, short and long term), *language* (receptive-comprehension, expressive, fluency, grammar, syntax), *perceptiveness* (visual, constructional, motor integration and knowing-gnosis) *social cognition* (recognition of situations/circumstances, emotions and consideration of others) and *motoric praxis* (integrity of learned movements, gesturing, understanding of commands & intentions) [5, 8]. Neurocognitive disorders can be acute, chronic, mild, moderate or severe and debilitating/terminal. DSM 5 classifies dementia as either Mild or Major Neurocognitive Disorder, then specify what it is due to and state whether with or without behavioral disturbance [8].

#### **4.5 HIV dementia**

Dementia of HIV infection has gone by many names including HIV-associated dementia (HAD), HIV encephalopathy, AIDS dementia complex, or HIV- associated neurocognitive disorder [40]. DSM 5 classifies it as Mild or Major Neurocognitive Disorder Due To HIV Infection [8]. The Frascati criteria described three cognitive sub-types based on 5 cognitive domains to establish the classification of the neurocognitive effects of the HIV virus on the brain as the HIV-Associated Neurocognitive Disorder (HAND) criteria [41]. The HAND criteria are useful in the identification of cases, monitoring of treatment and instituting caregiving especially in the severe form of the illness. The three HAND categories are Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND) and HIV-Associated Dementia, HAD as shown in **Table 2**.

In Africa, the prevalence of HAND, with or without ARV treatment was found to be 31% [42]. The prevalence was higher in females and with advanced immunosuppression as measured by low CD4 counts. Adherence to ARV treatment with immune


**Table 2.**

*Classification of HIV-associated neurocognitive disorder (HAND).*


#### **Table 3.**

*HAND subtypes prevalence in the pre and post ART era.*

reconstruction reduces the severity of HAND but does not eliminate it. Nevertheless, this is of utmost importance for PLWH in HIV care as advanced HAND impairs function and QoL. **Table 3** below shows the HAND subtypes prevalence in the pre and post ART era [37].

Screening for HAND is therefore of great importance in HIV care in PLWH. However the cognitive test performances and the tools used are often influenced by educational, cultural and socioeconomic factors. Sacktor et al. [42] reported on the IHDS as a culturally and educationally sensitive instrument for assessing HAD.

The mainstay of treatment for HAND is combination Highly Active Antiretroviral Therapy, HAART requiring a more than 90% adherence to the ARVs to ensure a very low or undetectable viral load, VL, in order to achieve the necessary immunosuppression. Individual and family psychosocial support is crucial in this exercise. This underscores the importance of integrating mental health care in any HIV care and prevention programs.

#### **4.6 HIV associated delirium**

The American DSM-5 diagnostic criteria for delirium are a an acute disturbance in attention and awareness that develops over a short period of time (hours to days) and representing a change from baseline, fluctuating in severity during the course of the day, with disturbances in cognition (memory, disorientation, language, perception) as a direct consequence of a medical condition, substance intoxication or its withdrawal, toxins or due to multiple etiologies [8]. Delirium in HIV/AIDS manifests clinically in the context of high viremia, advanced HIV disease, other infections, drug toxicities and substance abuse or metabolic disturbances [5]. The prevalence of delirium in of hospitalized HIV+ people may be as high as 30–40% [43] especially in those with advanced disease. Untreated delirium often leads to stupor, coma or death. The mortality rate of delirium can be as high as 20–40% [5, 43]. It is considered a medical emergency and diagnosing it and finding the cause(s) can be lifesaving.

A delirious person has disturbances in sleep continuity and presents as confused in relationship to time, the environment (location) and others, and the confusion waxes and wanes throughout the day, going in and out of a disoriented state, seeing things as they clearly are not, experiencing hallucinations and illusions and often paranoid thinking with behaviors of agitation, fear, anxiety, irritability, restlessness, anger and aggression. They cannot comprehend instructions. The delirium subtypes reflect psychomotor activity and include hyperactive delirium (agitated, hyperalert), hypoactive delirium (lethargic, hypoalert) and mixed states (combination of the two). Seizures are not uncommon in delirium. Dementia and depression must be excluded especially for hypoactive delirium.

Delirium is a medical emergency with a case fatality of 40% and thus calling for immediate hospitalization, sometimes to an intensive care unit [43]. Because of the ever-changing condition of the patient and to reduce external stimuli, delirious patients are managed in the hospital, in a quiet room with clear lighting, constant observation, regular monitoring of vital signs and psychiatric NOBS (Nursing Observation Sheet). The first priority in treating delirium is to ascertain patient safety as they are confused and often fall and injure themselves. They can be aggressive and cannot look after themselves in terms of steadiness, feeding, hygiene, toilet or even dressing. The second priority is to treat the underlying cause (hypoxemia, septicemia, anemia, metabolic and electrolyte imbalances, intoxications, medications, alcohol and illicit drug intoxications or their withdrawal etc.). Disorientation, aggression, paranoia, hallucinations, delusions and anxiety (fear) are treated with parenteral antipsychotic medications (haloperidol, risperidone, olanzapine) often combined with a benzodiazepine (Lorazepam, clonazepam), as tolerated by the patient [43]. Parenteral Thiamine is always administered in alcohol-related delirium. Delirium is frightening to the patient, family and friends. Repeated reassurance and re-orienting of the patient, explaining procedures and establishing a calm and constant environment and nurse/attendant are crucial. Providing a wall clock and calendar that the patient sees easily, and keeping the patient's room well-lighted during the day with dimmed lights at night are useful for patient orientation. For psychotherapy, on recovery, the patient and family are educated about the apparent cause of the delirium to avoid future risk e.g. substance abuse, non-compliance to ARVs and causing worsening of the HIV disease etc. [5, 43]. Psychotherapy helps alleviate the anxiety, guilt, anger, depression, or other emotional states and family dynamics. Prognosis of delirium is usually poor depending on its underlying cause with a fatality rate of 40% within a year of the delirium diagnosis.

#### **4.7 Substance abuse**

Substance abuse is defined as the use of illicit drugs and alcohol as well as misuse of prescription and over-the-counter medications [5]. Substances of common abuse in Africa include alcohol, marijuana, cathenone (khat), stimulants (amphetamines) and recently opiates (pain medications) and anxiolytics (benzodiazepines). Drug and alcohol abuse usually increases the indulgence into HIV infection risk behaviors including unsafe sex (multiple partners, unprotected sex), non-disclosure of HIV status to sex partners, sharing needles (in IV drug use) and passing HIV onto others [11]. Substance use leads to reduced judgment and compromises adherence to ART medications and increases chances of engaging in risky sexual behavior. Drugs and

*Psychiatric Problems in HIV Care DOI: http://dx.doi.org/10.5772/intechopen.106077*

alcohol also weaken the immune system, may interact with ARVs reducing efficacy or causing toxic side effects. Alcohol and drugs damage body organs including the liver which is responsible for drug metabolism. They may also lead to other mental disorders including delirium, seizures, depression and even dementia. They are also associated with family, social, educational, occupational and economic problems.

Treatment of drug and alcohol abuse begins with clinician suspicion and detection by direct inquiry and collateral information from family, friends and caretakers [5]. Drug screens and Liver Function tests such as GGT and pancreatic enzymes are helpful in pinpointing end organ (liver, pancreas) damage. Heavy substance dependence often needs hospitalization for medical detoxification followed by referral to Residential Rehabilitation programs for 3, 6, or 12 months and thereafter follow up aftercare for 1–2 years. Self-help support groups are helpful such as Alcoholics Anonymous, AA or Narcotics Anonymous, NA. Detoxification involves prophylactic treatment for withdrawal symptoms including tremors, sweats, rebound insomnia and anxiety and even psychotic symptoms and seizures. Any associated substanceinduced mental disorder such as anxiety, depression, psychosis or seizures is specifically treated. Family support is necessary to help the individual to stay totally abstinent from the substance of abuse.

#### **5. Conclusion**

Psychiatric problems associated with HIV/AIDS are many, varied and often bidirectional and they are often neglected. Their presence compromises HIV care and prevention efforts. Unaddressed, they compromise treatment outcomes, increase HIV virus resistant strains, leave pockets of potential HIV spread in the community and lead to poor quality of life and early death of PLWH. This calls for integration of mental healthcare in all HIV/AIDS treatment and prevention programs [44]. This chapter has focused on specific HIV-associated mental disorders. However, the mental health problems of HIV/AIDS go beyond disorders to include social, family and community problems such as the problems faced by AIDS orphans, widowhood, family disruptions, multiple deaths, bereavements, poverty, stigma, caregiver burden, education and occupational difficulties etc. All these need to be addressed in holistic HIV care. There is need for more research to address brain impairment in HIV/AIDS and its sequels and ways for total integration of mental health care in HIV care and prevention.

#### **Author details**

Seggane Musisi1,2\* and Noeline Nakasujja1

1 Makerere University College of Health Sciences, Kampala, Uganda

2 Entebbe Lakeside Hospital, Entebbe, Uganda

\*Address all correspondence to: segganemusisi@yahoo.ca

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 5
