Management of the HIV-Infected Woman
Rupa Kanapathipillai
Michelle L. Giles
Despite the dramatic advances in the treatment of HIV, the epidemic continues to soar, particularly among women. The growing number of women of reproductive age living with HIV is a dominant feature of this disease. HIV-infected women tend to be diagnosed later in the disease process than men and often have poorer access to HIV specialists and medications.1 They also may have specific vulnerabilities related to poverty, domestic violence, mental health, and responsibilities regarding children, some of whom may also be HIV-infected.2
Because most women of reproductive age are healthy, the only time they may visit a physician is for routine gynecologic care. Thus, it is important for the health care provider to be able to recognize the signs and symptoms that might suggest HIV infection so they can be diagnosed early in the disease. This allows for early intervention prior to the onset of opportunistic infections (OIs) with combination antiretroviral therapy (cART) in order to delay the progression to AIDS. In addition, the investigation and management of common gynecologic problems may need to be broadened if the woman is also infected with HIV.
This chapter provides an overview of the diagnosis and primary care of patients with HIV, along with issues unique to HIV-infected women that are related to the transmission of the virus, contraception, reproductive options, and gynecologic manifestations of the disease.
EPIDEMIOLOGY
HIV continues to be a major global health priority, with the proportion of women infected continuing to increase over the past 10 years.1, 2, 3, 4, 5 The World Health Organization (WHO) estimates that at the end of 2011, approximately 34 million people were living with HIV/AIDS, and of these, 16.6 million were women.1 There is geographic variation in HIV prevalence between and within countries. In 2011, sub-Saharan Africa accounted for 69% of HIV infections worldwide with 23.5 million people living with HIV/AIDS—approximately 60% of whom are women.1 Women account for 30 to 40% of people living with HIV/AIDS in Asia and Latin America, 30% in Eastern Europe and Central Asia, and 45 to 50% in the Caribbean.2
Women have a particular vulnerability to HIV, often compounded by cultural, social, and economic disadvantages.5 Studies show that women are more likely to acquire HIV from an infected partner during unprotected heterosexual intercourse than men.6 Genderbased violence and income inequality has also been associated with increased HIV risk.7, 8, 9 Economic disadvantage may increase high-risk behavior among women who may be driven to transactional sex by economic necessity, especially in the setting of migration.5,7 The rate of HIV infection among female sex workers is high in many parts of the world, many of whom may also use intravenous drugs.10
In the United States, the HIV epidemic has recently been described as “low prevalence in the general population, high prevalence among disenfranchised and socially marginalized.”3 It is estimated that there are now greater than 1 million HIV-infected Americans, more than 20% of whom are not aware of their diagnosis.11 At the end of 2011, 21% of new HIV infections in the United States were in females, predominately through heterosexual contact (86%). In 2011, Black/African American females made up 12% of the female population in the United States but accounted for an estimated 64% of diagnoses of HIV infection among females. Hispanic/Latino females made up 15% of the female population in the United States but accounted for 15% of diagnoses of HIV infection among females. White females made up 66% of the female adult and adolescent population in the United States but accounted for 17% of diagnoses of HIV infection among females.
The rate of new HIV infections among Black women in 2010 was 20 times that of White women and nearly 5 times that of Hispanic women (38.1 versus 1.9 and 8.0 per 100,000, respectively). Hispanic women experienced an HIV infection rate more than four times that of White women (8.0 versus 1.9 per 100,000). In 2011, the estimated rate of HIV infection classified as stage 3 (AIDS) among adult and adolescent females in the United States was 6.0 per 100,000 population. The rate of stage 3 (AIDS) classifications among Black/African American females (32.2) was 23 times as high as the rate for White females (1.4) and more than 5 times as high as the rate for Hispanic/Latino females (5.9).
In 2011, the majority of diagnoses of HIV infection among females aged 13 years or older were attributed to heterosexual contact regardless of age group. However, the percentages attributed to heterosexual contact decreased as age group increased. An estimated 17.4% of diagnosed HIV infections among females aged 45 years and older were attributed to injection drug use, compared with 7.0% in females aged 13 to 19 years, 8.8% in females aged 20 to 24 years, 12.7% in females aged 25 to 34 years, and 14.2% in females aged 35 to 44 years.
The largest percentage of new infections in 2010 occurred among people aged 25 to 34 years (31%; 14,500), followed by those aged 13 to 24 years (26%; 12,200), and those aged 35 to 44 years (24%; 11,300). An additional 15% (7100) occurred among people aged 45 to 54 years, and 5% (2500) among those aged 55 years and older.
The increased risk of HIV acquisition in particular subpopulations is more attributable to their vulnerable social and economic situation(s) and sexual network(s) rather than their own risky behavior.3 However, disproportionately high rates of sexually transmitted infections (STIs), including Neisseria gonorrhoeae, Chlamydia trachomatis, primary and secondary syphilis, Trichomonas vaginalis, and genital herpes amongst the black community may also contribute.12
SCREENING
Since the mid-1990s, major advances in the treatment of HIV has led to prolonged survival and improved quality of life for those living with HIV. Antiretroviral therapy (ART) during pregnancy has also led to a substantial reduction in perinatal transmission of HIV.13 The benefits of treatment for personal health outcomes and prevention of perinatal transmission can only be achieved if one is aware of his or her HIV status. Therefore, HIV testing for the early identification of infection is essential and opt-out screening is now recommended as a component of routine management in all health care settings in the United States.14
A higher percentage of patients have been found to test positive in settings such as hospitals and emergency departments (2 to 7%) using HIV screening than at publicly funded HIV counseling and testing sites (1.5%) and STI clinics (2.0%) serving patients perceived at high risk for HIV.14,15 Targeted testing on the basis of risk factors fails to identify a substantial number of people who are HIV-infected,16, 17, 18, 19 further supporting the recommendation for universal testing with informed consent.
The Centers for Disease Control and Prevention (CDC) recommends diagnostic HIV testing and opt-out HIV screening in all health care settings for patients aged 13 to 64 years with the onus on health care providers to initiate screening unless the prevalence of undiagnosed HIV infection in their patients has been documented as less than 0.1% (or until diagnostic yield is less than 1 per 1000 patients screened).14 In addition, all patients initiating treatment for tuberculosis (TB) or seeking treatment for an STI should be routinely screened for HIV.14 Routine HIV testing obviates the need for provider-dependant assessment of risk, is associated with reduced stigma and is accepted more widely by patients,20 including women especially if they perceive that their health care provider strongly recommends the test.21
Providers of reproductive health care play an important role in identifying women at risk of, or infected with, HIV. These providers are particularly well suited to screen for HIV because the same issues that bring women to them, both sexual and reproductive health, provide an opportunity for discussion of potential exposure to HIV. Early diagnosis of HIV infection can have an enormous beneficial impact on the health and survival of these women along with potentially reducing risk of transmission to sexual partners and future offspring.
HIV screening should be a routine part of preconception care, providing women with maximal opportunity to know their HIV status prior to conception. A substantial proportion of the estimated 144 to 236 perinatal HIV infections per year in the United States are due to lack of timely HIV testing and treatment of pregnant women.22,23 Multiple barriers to prenatal HIV testing have been identified24—health care providers’ perceptions that their patients are at low risk for HIV25,26 lack of time for counseling and testing,25,26 lack of patient education materials,26 lack of provider knowledge/training,25,26 concern about managing a woman who refuses testing,25 concern about informing a patient of his or her HIV positive status,25 and knowledge of state regulations.27
Screening should be voluntary and undertaken only with the patient’s knowledge and consent. Oral or written information dependant on local statutory requirements28 should be provided to the patient and the opportunity to ask questions be facilitated. Information should be provided in clear, simple language, appropriate to the first language of the patient and interpreters should be used if required. The CDC advocates that general informed consent for medical care is considered sufficient to encompass informed consent for HIV testing and that specific signed consent for HIV testing is not required.14 Certain states, however, may have specific requirements for counseling, written consent, confirmatory testing, or communicating HIV results and health care providers should be aware of these in case they preclude adoption of the CDC recommendations.28,29
In the prenatal setting, screening has proven substantially more effective than risk-based testing for detecting unsuspected maternal HIV infection and preventing perinatal transmission.14 When offered, 75 to 95% of pregnant women accept HIV testing.30 Universal HIV screening in early pregnancy is recommended in many resource-rich countries31, 32, 33 and any woman with undocumented HIV status at time of labor should be screened with a rapid test if available unless she declines. On the basis of a positive rapid test result immediate initiation of
appropriate antiretroviral prophylaxis is recommended, without awaiting confirmatory testing.13
appropriate antiretroviral prophylaxis is recommended, without awaiting confirmatory testing.13
DIAGNOSTIC TESTING
Diagnostic testing for HIV infection is composed of detecting antibodies to components of the virus, usually followed by a confirmatory test called a Western blot. At times, tests for HIV RNA or DNA may also be included in diagnostic algorithms. More recently, rapid HIV diagnostic tests have been licensed for use and are particularly relevant to the prenatal setting.
About one-third of HIV-infected patients receive their first positive diagnostic test within 1 year of an AIDSdefining illness, which implies they have been infected for approximately 7 years prior to the testing.34 Studies show that about 41% of patients infected with HIV are diagnosed on their first test, whereas 59% are diagnosed within 1 to 2 years after an initial negative test.35 For these reasons, it is important that those at increased and ongoing risk be advised to undergo repeat testing. From a population perspective, testing based on risk factors alone has failed to identify a large number of people with HIV infection because many individuals do not declare their risks, do not think they are at risk, or avoid testing due to stigma.36
In 2012, the U.S. Preventive Services Task Force (USPSTF) released preliminary recommendations for universal HIV screening among patients aged 15 to 65 years; the American College of Physicians (ACP) Guidance Statement on HIV screening similarly endorses universal screening, although they suggested the age range be expanded to 75 years, due to the growing number of HIV infections in older patients.37,38
Routine testing is implemented through a strategy called “opt-out testing,” whereby the patient is informed orally, or in writing, that HIV testing will be performed but has the option of declining or deferring the testing.
Each HIV particle is composed of an envelope containing glycoproteins (gp120 and gp41) that surrounds the HIV RNA genome. The gp120 and gp41 glycoprotein molecules are associated with several other proteins that are essential for HIV propagation and survival; reverse transcriptase, which converts HIV RNA to DNA, and integrase, which facilitates the integration of HIV DNA into the host’s cell genome. These proteins and glycoproteins evoke an immune response from the infected host.39
HIV-1 and HIV-2 are two related virus that can both cause AIDS in humans (see section on HIV-2 later in chapter). Multispot HIV-1/HIV-2 Rapid Test (BioRad laboratories) is a U.S. Food and Drug Administration (FDA)-approved diagnostic test used for differentiating HIV-1 from HIV-2 infection but commercially available HIV-1 viral load (VL) assays do not reliably detect or quantify HIV-2 VL.40, 41, 42
Antibodies to gp41 (envelope protein) and p24 antigens are the first detectable serologic markers following HIV infection.43 The model established by Fiebig et al.44 using plasma samples from donors, reported the window period for HIV RNA, p24 antigen, and anti-HIV antibodies as 12 days, 17 days, and 22 days, respectively. Viremia can be reliably detected within the first 2 weeks of infection with HIV and increases logarithmically during an initial “ramp-up” phase.45 Approximately 1 month after the onset of infection, second- (IgG antibody sensitive) and third- (IgM antibody sensitive) generation immunoassays can detect early antibody responses to the virus.45 IgG antibodies appear 6 to 12 weeks following HIV infection in the majority of patients and by 6 months in 95% of patients46 and generally remain detectable for life. Diagnostic tests that rely on antibody alone may not detect cases of early, acute HIV infection, when the patient is most infectious. Therefore, fourth-generation immunoassays (which combine antibody and p24 antigen detection) and HIV nucleic acid amplification tests (NAATs) may be more reliable in detecting acute HIV infection.45
HIV screening tests can be divided into the following:
Antibody (+/— antigen tests)
Confirmatory test (Western blot)
Virologic tests (HIV RNA or proviral DNA)
Rapid tests
Most testing algorithms require the use of specific confirmatory assays, such as the Western blot, to verify reactive antibody screening test results.47 Clear explanation should be given about the meaning of the reactive test result; emphasis should be placed on the importance of confirmatory testing and the importance of taking precautions to avoid the possibility of transmitting infection to others while awaiting results of confirmatory testing.
Antibody (+/— Antigen Tests)
The most common method of HIV screening is with an enzyme-linked immunosorbent assay (ELISA) test to detect antibodies against HIV. Results are reported as negative, positive, or indeterminate. A positive HIV test result is made based on a repeatedly positive ELISA followed by a positive Western blot. The sensitivity and the specificity of the ELISA are both greater than 99%.48 False-negative ELISA results most commonly occur at the time between viral transmission and seroconversion during acute infection. This “window period” can last approximately 3 to 6 weeks, during which time antibody levels are not yet detectable by third-generation testing methods.48 This window period is reduced by the fourth-generation ELISA combining detection of antibodies with HIV antigens.49 Fourth-generation enzyme or chemiluminescent
immunoassays were engineered for dual detection of p24 antigen and HIV antibodies and can detect acute HIV infection before current standard ELISAs.45 At the time of writing, these antigen-antibody tests were widely available in Europe and Australia, with recent introduction into Latin America but have not yet been approved by the FDA for use in the United States.50
immunoassays were engineered for dual detection of p24 antigen and HIV antibodies and can detect acute HIV infection before current standard ELISAs.45 At the time of writing, these antigen-antibody tests were widely available in Europe and Australia, with recent introduction into Latin America but have not yet been approved by the FDA for use in the United States.50
The ELISA kits for screening in the United States and Europe detect all M subtypes but do not consistently detect other groups.48 False-negative results can occur rarely in the setting of immune dysfunction due to defective humoral response or agammaglobulinemia, immunosuppression due to malignancy or medication, delay in seroconversion following early initiation of ART, or fulminant HIV infection.48 False-positive ELISA results have been reported in patients with autoantibodies, such as autoimmune diseases, liver disease, hemodialysis, multiparity, transfusion, renal disease, or vaccinations, including those enrolled in HIV vaccine trials.45,51
Confirmatory Test (Western Blot)
The Western blot (WB) is the most widely accepted confirmatory assay for diagnosing HIV infection. A purified HIV antigen mixture including core (gag) (p17, p24, p55), polymerase (pol) (p31, p51, p66), and envelope (env) (gp41, gp120, gp160) proteins48 is layered onto a gel slab and electrophoresed. These HIV antigens undergo migratory separation determined by electrical charge and molecular weight. The WB assay detects antibodies to these specific antigens and produces a colored band wherever an antigen-antibody complex is found. Reaction with a positive serum sample produces a pattern of bands characteristic for HIV. A WB is positive if reactivity is detected to gp41, p24, or gp120/160.48 The presence of one or more bands that do not meet these criteria for a positive result is considered an indeterminate Western blot (IWB) result. The significance of IWB result varies depending on risk factors, clinical status of the patient, and the WB profile. Patients with IWB results should be retested within 1 to 3 months based on the clinicians’ assessment of risk factors. They should be counseled to avoid activities that could transmit the virus until repeat testing is performed. In the setting of possible acute HIV infection, WB testing has a sensitivity of 99.3% and a specificity of 99.7%.48
Virologic Tests (RNA or DNA)
Other methods to establish HIV infection include viral isolation by qualitative and quantitative detection of HIV through polymerase chain reaction (PCR), branched DNA testing or nucleic acid sequence-based amplification. These tests can report the number of copies of virus per milliliter of plasma. The lower limit of detection for standard tests is 400 copies/mL, but ultrasensitive assays can detect as few as 20 to 50 copies/mL.52 Because the tests are expensive and technically complex to perform, they have not been adopted as screening tools.51 Viral detection, either by DNA or quantitative RNA should not be used alone for diagnosis. The use of quantitative RNA (VL) assays has not been approved by the FDA for diagnosis of HIV infection. A low positive HIV RNA level (less than 5000 copies/mL) may represent a false-positive result. Because of concerns over false-positive results, patients with HIV infection diagnosed on the basis of RNA testing should have serologic testing performed at a subsequent time to confirm seroconversion.51
Rapid Tests
Rapid testing is particularly helpful for those with only sporadic interactions with health care providers. Results are reported as positive, negative, or indeterminate. Six rapid HIV tests have now been approved by the FDA with sensitivities of 99.3 to 100% and specificities of 99.1 to 100%.53
HIV antibodies, if present, bind to HIV antigens affixed to the test strip creating a visually detectable indicator conferring a positive result. Advantages of rapid tests include point-of-care diagnosis, with preliminary results being available to the patient within minutes rather than days to weeks. Cost analyses report that rapid point-ofcare testing is cheaper per test result delivered when compared with standard blood testing.50 False-positive results have been reported in patients screened with oral fluid tests54 and a repeatedly false-negative result has been reported in a patient with advanced HIV.55
A positive screening rapid test result requires confirmation with a supplemental test such as a WB. If confirmatory testing is negative or indeterminate, follow-up testing after 1 month is recommended.
As a result of the high sensitivity and specificity of rapid tests, a negative rapid test result can be disclosed to the patient as conclusive. However, retesting in 3 months’ time with either a rapid test or ELISA is recommended in persons with a possible exposure within the past 3 months due to the delay in formation of detectable antibodies.51
The Association of Public Health Laboratories and the CDC have proposed several algorithms to allow for various combinations of screening and confirmatory tests.14 The WHO has developed algorithms, for use in resource-constrained settings, for the definitive diagnosis of HIV infection that is composed of two or three different rapid tests in combination.56
Rapid Tests for HIV in Pregnancy, During Labor, and at Delivery
Ideally, all women should be screened for HIV as part of prepregnancy management so they know their HIV status prior to conception. Screening in early pregnancy enables HIV-infected women and their infants to benefit from interventions such as antiretroviral medication; scheduled cesarean delivery, if at all possible; and avoidance of breast-feeding.14
Although knowledge of the mother’s HIV status provides opportunities for interventions that reduce perinatal HIV transmission, many women present to the health care system at the time of labor without knowledge of their HIV status.57
The MIRIAD Study,58 a multicenter prospective study addressing feasibility, acceptance, and performance of rapid testing among women in labor, compared ELISA to a rapid test (Ora-Quick Rapid HIV-1 Antibody Test) in 4849 women with unknown serostatus who presented late in pregnancy or in labor. Acceptability of testing was high with 4849/5744 women (84%) agreeing to a test.58 Of 38 women with reactive HIV rapid tests, 4 were found to be false positive, with no false-negative results when confirmed with WB.58
One advantage of rapid HIV tests is the potential to increase the number of individuals who are tested and receive results. Although there is the problem of falsepositive results, the majority of women (HIV negative) can receive this result immediately. A recent systematic review and meta-analysis of rapid point-of-care HIV testing in pregnant women found that overall sensitivity ranged from 75 to 100% and specificity varied from 96 to 100%.56 In four studies, a significant improvement in sensitivity and specificity estimates were reported with the use of a sequential rapid testing algorithm,59 and one study reported parallel testing as superior to serial testing.60
ACUTE AND EARLY INFECTION WITH HIV
Acute HIV may present as a syndrome reminiscent of mononucleosis and include a myriad of nonspecific symptoms, such as fever, nontender lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache. Occasionally, patients may also complain of mucocutaneous ulcers. This constellation of symptoms is also known as the acute retroviral syndrome but it is not seen in all patients in the early stages of HIV infection, that is, the first 6 months after acquiring HIV. For 10 to 60% patients, the early stages of infection may be asymptomatic.61 In patients who do have acute, symptomatic infection, the time lapse from HIV exposure to the development of symptoms is 2 to 4 weeks, although incubation periods may last longer. It is not clear if the mode of acquisition and/or quantity of viral inoculums impacts the length of the incubation period.
The presence of acute retroviral syndrome, duration of symptoms for more than 14 days, and increased severity of the symptoms, has been linked to a more rapid progression to AIDS and poorer prognosis; in one study of 218 female sex workers with well-documented seroconversion dating, each additional symptom at the time of acute infection was associated with an increasing risk of overall mortality.62, 63, 64
Fatigue, myalgia, and fever ranging from 38 to 40°C are the most common symptoms in the acute HIV infection phase. A rash may erupt 48 to 72 hours after the fever starts and usually lasts for 5 to 8 days. The rash typically involves the upper half of the chest, neck, and face, although the scalp, palms, and soles may also be affected. The macular or maculopapular lesions are usually small (5 to 10 mm), well-circumscribed, ovoid, and pink to deep red. In some cases, vesicular or pustular lesions may be noted. Nontender adenopathy involving the axillary, cervical, and occipital nodes are common. Although the nodes will decrease in size over time, a modest degree of enlargement usually persists. Mild hepatosplenomegaly may be noted. Patients often complain of a sore throat and there may be edema and hyperemia of the pharynx; enlargement or exudates on the tonsils is not common. Painful mucocutaneous ulcers involving the mouth, esophagus, genitals, or anus is a distinctive manifestation of acute HIV infection. Gastrointestinal (GI) symptoms such as nausea, diarrhea, anorexia, and weight loss are common. Headaches are usually retroorbital and eye movement may intensify the pain.
Acute HIV infection is a period of rapid viral replication and infection of CD4 T cells, and VLs may be quite high, for example, more than 100,000 up to more than 1 million copies/mL; there may be a transient decline in the CD4 cell count. Leukocyte and lymphocyte counts vary during the acute infection, and initially, the total white blood cell (WBC) count may drop, but as the number of lymphocytes expands, the WBC count will increase. CD8+ lymphocytes increase at a faster rate than CD4+ T lymphocytes, and this results in a persistent inversion of the CD4 to CD8 ratio that is less than one.
The diagnosis of acute HIV infection is established by the detection of HIV viremia, either through a viral RNA or p24 antigen test, in the setting of a negative or indeterminate HIV serologic test pattern in a patient with clinical features suggestive of the acute retroviral syndrome. Detectable viremia does not develop until approximately 10 to 15 days after infection, and even the most sensitive immunoassays do not become positive until 5 days after that. The reverse transcriptase polymerase chain reaction (RT-PCR) test is not approved by the FDA for HIV RNA detection in the evaluation for early HIV infection but it is highly sensitive and specific. A false-positive test should be suspected if the VL is low (less than 10,000 copies/mL) in the presence of acute retroviral syndrome symptoms. If this occurs, a repeat sample should be drawn and if it too is positive, this is suggestive of a true positive result.65 The p24 antigen becomes positive approximately 5 to 7 days following the detection of viral RNA.66,66a After a diagnosis of acute or early HIV infection is made, patients should ideally be referred to a provider with experience in HIV management.
Some HIV-infected patients (4 to 7%) remain asymptomatic over many years (more than 10 years) without ART and are referred to as “long-term nonprogressors.”67 “Elite controllers” are HIV-seropositive individuals who are not on therapy but have no evidence of viremia, as measured by standard assays (either less than 50 or less than 75 copies/mL), and maintain high CD4 cell counts. “Viremic controllers” have low levels of detectable viremia.
FACTORS AFFECTING PROGRESSION OF HIV INFECTION
The average life expectancy for a HIV-infected patient in the absence of treatment is approximately 10 to 12 years, although the rate of HIV progression varies greatly between individuals in the absence of ART. The CD4 count and plasma VL are two important and independent laboratory determinants of the rate of progression of HIV infection. Of the two, the CD4 cell count is the strongest predictor of disease progression and survival.68 The average rate of CD4 cell decline or CD4 slope is about 50 cells/mm3 per year and the average viral burden (without therapy) is 30,000 to 50,000 copies/mL.
Genetic regulation of immunologic control of HIV and medication adherence are the two most important factors in the rate of disease progression, although other factors that negatively impact progression have been identified (Table 27.1). As CD4 cell counts decline, the risk of OIs increases. Various CD4 count thresholds are used to determine when prophylaxis for various OIs, such as Pneumocystis pneumonia (PCP), toxoplasmosis, Mycobacterium avium complex (MAC) infection should be initiated.
TABLE 27.1 Factors That Influence the Rate of Progression of HIV Infection | ||||||||||||||||||||||||||||||||||
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There are now four treatment strategies that are known to prolong survival:
ART
Pneumocystis carinii prophylaxis
M. avium prophylaxis
Care by a physician with HIV-care experience
PRIMARY HIV CARE
The focus of this section is to illustrate general principles of evaluation and establish a basic template for evaluation of the HIV-infected woman. It is beyond the scope of this chapter to discuss clinical staging of HIV and manifestations of various OIs; however, comprehensive guidelines regarding aspects of care of HIV-infected persons are widely available.69
For the majority of women of reproductive age, a visit for a routine annual exam or gynecologic problem may be the only opportunity for HIV testing and assessment of the potential gynecologic manifestations of HIV. Thus, reproductive health care providers are in a unique position to both diagnose and manage these complications. The prevalence and incidence of gynecologic problems are high in HIV-infected women.70, 71, 72
Due to the medical and social complexity of HIV, a multidisciplinary approach to care is essential. The primary care provider is often best suited to perform the initial evaluation and coordinate referrals to specialty providers. Better clinical outcomes have been reported in patients managed by an experienced HIV medical provider.73, 74, 75 The importance of continuing gynecologic follow-up should also be emphasized because a large number of women still do not receive gynecologic care from their HIV specialist.76 During the initial evaluation, assessment of support systems should be made for each patient and clear, nonjudgmental communication, sensitivity, and confidentiality are essential.
Clinical Assessment of HIV
A comprehensive evaluation of the HIV-infected woman includes a thorough history and physical examination, including pelvic exam, laboratory tests, and psychological and social support assessment.69,77
History (HIV Specific)
Date of diagnosis; prior negative test results
Possible routes of exposure
HIV-related symptoms/OIs
HIV-associated complications and comorbidities; malignancies, cardiovascular disease history/risk
Lowest CD4 cell count documented
Previous antiretroviral or prophylactic therapies; duration of treatment, side effects or complications, response, results of resistance testing, adherence
HIV-related symptoms including fever, night sweats, weight loss, headaches, visual changes, oral thrush/ulceration, respiratory symptoms, diarrhea, skin rashes, changes in neurologic function/mental status.
History (Other Medical)
Chronic medical conditions; for example, peripheral neuropathy, GI disease, chronic viral hepatitis, renal impairment, bone disease
Previous TB/TB exposure
History (Gynecologic)
Menstrual history
Sexual practices
Contraception
Condom use history
Previous sexually transmitted and other genital tract infections
Prior abnormal Pap smears
Other gynecologic illnesses or symptoms
History (Medications/Allergies/Vaccinations)
Current medication—including prescription/over-thecounter/dietary or herbal supplements
Allergies—hypersensitivity to previous therapies, including sulfonamides
Vaccination history, including tetanus toxoid/pneumococcal vaccine/hepatitis A and B vaccines
History (Social and Family)
Drug and alcohol use
Support systems
Disclosure history
Current employment
Relationship status
Child care responsibilities
Depression and domestic violence screening
Physical Examination (General)
General appearance; vital signs, height, weight
Skin—check for any rashes, for example, seborrheic dermatitis, Kaposi sarcoma, folliculitis, fungal infections, psoriasis
Body habitus—drug-related lipodystrophy
Fat accumulation—increased dorso-cervical fat pad, gynecomastia, abdominal protuberance (visceral fat)
Lipoatrophy—loss of subcutaneous fat in the face, extremities, or buttocks
Fundoscopy—refer to ophthalmologist for review in those with advanced HIV (CD4 less than 50 cells/mm3) and those with ocular symptoms.
Oropharynx—check for thrush (candidiasis), oral hairy leukoplakia, mucosal Kaposi sarcoma, aphthous ulceration, periodontal disease.
Cardiopulmonary examination
Abdominal exam—examine for hepatomegaly or splenomegaly.
Persistent generalized lymphadenopathy; localized lymphadenopathy, hepatomegaly or splenomegaly
Neurologic examination—perform a general assessment of mental status, cognitive function, coordination, memory, and motor and sensory testing (there is an HIV dementia scale available if the exam suggests HIV-associated dementia).
Breast examination
Physical Examination (Pelvic)
Visual inspection of vulva and perineum—genital ulcers, warts, or other lesions
Speculum examination—look for abnormal vaginal discharge, vaginal/cervical lesions.
Bimanual and rectovaginal examination—rule out cervical, uterine, adnexal, and rectal tenderness/masses.
Pelvic examination should be performed annually. This may be performed more frequently if there is a history of abnormal Pap smears, unsafe sexual practices, exposure to STIs or development of gynecologic signs or symptoms. STI screening should be performed when the patient reports recent or ongoing high-risk sexual activity. Pelvic examination every 6 months may be considered in women with clinically advanced disease, low CD4 cell counts, and/or high VLs because their incidence of certain HIV-related gynecologic problems may be increased.77
Laboratory
Patients found to be infected with HIV should also be screened for exposure to or latent infection with other infections (Table 27.2).
An assessment of the woman’s immunologic and virologic status should be done on a regular basis. Any patient with a CD4 count less than 200 cells/mm3 should be assessed for primary OI prophylaxis according to guidelines.78 Patients should be referred to an HIV specialist for consideration of ART and long-term virologic follow-up.
Selected Primary Care Issues and HIV Infection
Approximately 30% of HIV-infected patients in the United States are coinfected with hepatitis C virus (HCV), and about 8% are coinfected with hepatitis B virus (HBV).79 Liver disease tends to progress more rapidly in patients with HCV and HBV concurrently infected with HIV/HCV compared with those with HCV or HBV infection alone. Some ART therapies have both anti-HIV and anti-HBV activity.80
Despite lower rates of obesity among HIV-positive women, the rates of hyperglycemia are almost double that of HIV-negative women, particularly among HIV-infected Hispanic and Black women.81,82 As a result, diabetes must be considered in the preventive care HIV-infected women receive.
TABLE 27.2 Screening for Other Infectious Diseases | ||||||||||||||||
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There is a greater risk of coronary artery disease in HIV-infected patients, especially for those on protease inhibitors, which increase the likelihood of developing glucose intolerance and/or dyslipidemia.83 If coronary artery disease is diagnosed, management should be initiated according to accepted practices.
HIV infection is a very significant risk factor for reactivation of latent TB, and patients with a positive PPD are at high risk for developing active infection in the absence of prophylaxis. HIV infection is also associated with accelerated progression of TB and extrapulmonary involvement.
HIV-infected patients should be advised to avoid eating raw eggs, unpasteurized dairy products, raw seafood, and undercooked meat.
Immunizations
In general, immunizations should also be given according to current CDC guidelines.84 All inactivated vaccines are acceptable to use with HIV infection, but live-attenuated vaccines should be avoided, although some live vaccines (e.g., varicella) are recommended in HIV-infected patients with CD4 cell counts greater than 200 cells/mm3. Close contacts of HIV-infected patients should receive all age-appropriate immunizations with the exception of oral polio and smallpox vaccines.
Pneumococcal pneumonia and meningitis are leading causes of morbidity and mortality among HIV-infected patients, and because of the increasing incidence of drug-resistant pneumococcal strains, it is getting harder to treat them. The most important risk factor for developing pneumococcal infections is the level of immunosuppression (e.g., CD4 count less than 200 cells/mm3). All HIV-infected patients with a CD4 count greater than 200 cells/mm3 should receive pneumococcal vaccine. If the CD4 count is lower, the vaccine may not be as effective. Revaccination should be considered 5 years after the initial vaccination or sooner if it was administered when the CD4 count was less than 200 cells/mm3 and the CD4 count is greater than 200 cells/mm3 on ART.
All HIV-infected patients should receive influenza vaccination annually. The inactivated vaccine formulation is recommended; intranasal vaccines should not be used in immunosuppressed patients.
The hepatitis B vaccination series should be administered to all HIV-infected patients who do not have serologic evidence of current or prior HBV infection. Due to a reduced response rate to the vaccine in HIV-infected patients, a postvaccination hepatitis B surface antibody (HBsAb) titer is recommended 1 to 6 months after the series is completed. Revaccination should be considered for those who lack evidence of serologic response to the initial series.85
Hepatitis A vaccination should be administered to patients with specific risk factors early in the course of HIV infection or after immune reconstitution with ART.
The response to the polysaccharide meningococcal vaccine is suboptimal among patients with HIV but it should be given to HIV-infected adults with functional or anatomic asplenia, travel exposure, are of college age, or living in dormitories. HIV-infected individuals should receive two doses, with the second dose administered 8 weeks or more after the first dose, plus booster doses every 5 years.
The American Academy of Pediatrics recommends the MMR vaccine be given to HIV-infected patients, except those who are severely compromised, whereas Advisory Committee on Immunization Practices (ACIP) recommends that only HIV-infected patients with CD4 counts greater than 200 cells/mm3 should receive it.86,87
Because there is a risk of disseminated TB disease after vaccination, and the efficacy of BCG vaccine is unknown, BCG immunization is not recommended in HIVinfected patients.
HIV IN ADOLESCENTS
Adolescents and young adults accounted for approximately one-fourth of new HIV infections in 2010, and approximately one-third of new infections in adolescents occur in females.88 The number of HIV-infected adolescents who acquired their infection perinatally is also increasing and it is important to recognize that the needs of these adolescents are quite unique. The primary mode of HIV acquisition in adolescents is through high-risk sexual behavior.
Pretest counseling of adolescents needs to include a discussion that if the initial test is negative, there is still a need to retest if the reason for the testing is risky behavior. Understanding the adolescent’s psychological level of maturation and any issues they may have as well as their social and economic support systems will be critical to developing successful treatment and prevention plans. Generally, an adolescent can seek HIV testing and treatment without the consent of a parent but it is helpful to discuss with them who they would rely on if the test were positive. Risk reduction strategies should be included in any pretest counseling session.
Ideally, the same person who did the pretest counseling will also discuss the results with the adolescent in a private and secure setting. If the test is negative, reinforcement on risk reduction and plans to protect themselves from HIV should be given. If the test is positive, close follow-up should be scheduled and the patient should be asked if he or she would like assistance in disclosing the results to trusted adults and/or partners.
One of the biggest issues in treating HIV-infected adolescents is compliance with ART. Poor adherence increases the risk of viral resistance as well as viral rebound. Psychosocial factors play an important role in adherence so evaluating the adolescent for comorbidities such as mental illness or substance abuse, developmental issues, their ability to manage complex schedules of drugs, their living situation, and a source of adult support is very important.
The physical exam and lab testing should determine the Tanner stage of development (which will help determine drug dosing), screening for other STIs, a Pap smear, and serology screening for varicella. If they are negative for varicella immunity, then immunization is indicated but as it may temporarily increase VL, it should be given after VL testing is done.
Treatment should be given by an expert in the care of adolescents with HIV.
TREATMENT OF HIV
All patients with early HIV infection should undergo drug resistance testing, regardless of whether treatment is going to be started or not as 15 to 20% of patients may be infected with an isolate carrying at least one drug resistance mutation and some mutations become undetectable over time89, 90, 91, 92 (Table 27.3).
There are two types of HIV resistance tests available. Genotypic testing identifies specific resistance mutations in the individual’s HIV genome and is interpreted using rule-based algorithms. Phenotypic testing is a measure of the ability of the patient’s virus to replicate in the presence of specific antiretroviral drugs and may be the preferred test in patients who are highly treatment-experienced with a history of multiple resistance mutations. Phenotypic testing is more expensive than genotypic testing.
If treatment is initiated (immediately or later), the selection of treatment regimens should take into account any initially detected resistance mutations. Drug resistance may be specific to a particular drug and not
necessarily an entire class and in some instances, resistance to one drug may increase susceptibility or decrease susceptibility to another drug.93,94 The use of phenotypic and phenotypic susceptibility testing leads to better viral suppression and has been associated with better survival.95,96 A specialist experienced in the management of HIV infection and interpretation of drug resistance testing should be consulted.
necessarily an entire class and in some instances, resistance to one drug may increase susceptibility or decrease susceptibility to another drug.93,94 The use of phenotypic and phenotypic susceptibility testing leads to better viral suppression and has been associated with better survival.95,96 A specialist experienced in the management of HIV infection and interpretation of drug resistance testing should be consulted.
TABLE 27.3 Contributing Factors to HIV Drug Resistance | ||||||||||||
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HIV treatment guidelines from the U.S. Department of Health and Human Services (DHHS) and the International Antiviral Society-USA (IAS-USA) panels now recommend antiretroviral treatment in all patients with HIV infection, regardless of CD4 cell counts.68,97 Once started, ART is continued indefinitely. Clinicians are not able to accurately assess which patients will be adherent to ART regimens, so patients should not be denied ART based solely on a history of psychiatric illness or chaotic lifestyles.
The initiation of ART can lead to a microbe-specific inflammatory response called the “immune reconstitution inflammatory syndrome” or IRIS, among those with undiagnosed OIs, for example, pulmonary TB or cryptococcal meningitis. For this reason, a complete review of systems should be performed, particularly in the patient with advanced AIDS. Shortly after starting ART, patients with underlying cytomegalovirus (CMV) retinitis may develop immune recovery vitreitis, a condition characterized by a decline in visual function.
There are six major classes of drugs used to treat HIV infection and over 20 antiretroviral medications within these classes (Table 27.4). An ART regimen is described as having a “backbone” and a “base.” The backbone typically consists of two nucleoside reverse transcriptase inhibitors (NRTIs). The base has traditionally included either a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI), although raltegravir, a drug from the integrase inhibitor class is also a possible base option. ART regimens should have at least three active antiretroviral medications; regimens with more than three drugs are not more efficacious and are associated with more side effects.98 Regimens with three different classes of drugs are no more potent than regimens made up of two different classes of drugs99 (Table 27.5).
Nucleoside analogs, or NRTIs, are considered the backbone of ART and are generally used in combination with an NNRTI, PI, or integrase inhibitor. NRTIs are usually given in pairs, such as tenofovir and emtricitabine, abacavir and lamivudine, and zidovudine and lamivudine.97 All of these combinations are available as coformulations; Truvada (tenofovir-emtricitabine), Combivir (zidovudinelamivudine), and Epzicom (abacavir-lamivudine), respectively, which helps to reduce pill burden and improve drug adherence. The DHHS guidelines panel recommends tenofovir-emtricitabine as the preferred nucleoside analog coformulation in combination ART for the treatment-naive patient because of its overall potency, favorable toxicity profile, and convenience of dosing.68 Tenofovir-emtricitabine is also the preferred agent for HIV-infected patients with concomitant hepatitis B virus infection.
TABLE 27.4 Classification of Antiretroviral Drugs | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Ritonavir is a potent inhibitor of the hepatic enzyme CYP (450) 3A4. This characteristic is used to “boost” the serum concentration of other PIs, which improves their trough serum concentrations and rates of viral suppression; use of ritonavir also enables lower dosing of the parent drug, thereby decreasing pill burden for the patient. When used at doses of 400 mg/day, ritonavir is not viewed as an active ingredient in any ART regimen,
it is only a pharmacokinetic booster for other drugs. Full doses of ritonavir (600 mg/day twice a day) are associated with too many adverse events for it to be a mainstay of ART. Using ritonavir as a booster is associated with adverse effects such as hyperlipidemia, drug interactions, and GI intolerance; these effects are dose related.
it is only a pharmacokinetic booster for other drugs. Full doses of ritonavir (600 mg/day twice a day) are associated with too many adverse events for it to be a mainstay of ART. Using ritonavir as a booster is associated with adverse effects such as hyperlipidemia, drug interactions, and GI intolerance; these effects are dose related.
TABLE 27.5 Guidelines for Antiretroviral Therapy Regimens for Initial Treatment of HIV Infection | ||||||||||||||
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Studies have shown that ART regimens based on NNRTIs or ritonavir-boosted PIs, with a backbone of two NNRTIs are comparable for the treatment of HIV.97
The management of ART is complex and should be delivered by providers with specific training. One study, done in the mid-1990s demonstrated a 31% reduction in the risk of death when HIV-infected patients were treated by physicians with a great deal of clinical experience with this disease.100
Adverse Effects of Antiretroviral Therapy
ART drugs are extremely potent and are known to be associated with adverse effects ranging from mild to life-threatening. Some reports suggest that ART drugs may evoke different treatment responses in women compared to men, and there are some considerations when treating women with HIV, for example, differences in risk for treatment complications, drug-drug interactions, tolerability, and the possibility of pregnancy (Table 27.6).101, 102, 103 General intolerance to ART agents appears to be more common in women than men and leads to increased discontinuation rates. Women are at greater risk for the syndrome of rash and hepatic failure with nevirapine, a higher incidence of rash with efavirenz, and higher risk for lactic acidosis with some nucleoside analogs, especially stavudine and didanosine.61,104,105
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