CHAPTER 37

HIV/AIDS

Agnes Cha, PharmD, BCACP, AAHIVP

The understanding of AIDS and management of the causative HIV have evolved dramatically over the past 30 years. The impressive advancement of antiretroviral therapy (ART) has directly led to decreased mortality, improved survival, and sustained virologic control. As a result, HIV has become another chronic disease state to manage. Moreover, HIV-infected individuals can have approximately the same life expectancy as those not infected with HIV (vanSighem, Gras, Reiss, Brinkman, & de Wolf, 2010). It is estimated that by 2015, nearly half of the HIV-infected population will be older than 50 years.

Because it is not feasible for infectious disease specialist clinicians alone to manage the care of this expanding population of patients, it is inevitable that primary care clinicians will encounter patients with HIV in their practices. Thus, it is important to maintain a working knowledge of HIV management. This chapter provides an overview of HIV from a primary care perspective. With the fundamental comprehension of ART, its adverse effects, and preventative care strategies, the primary care provider can provide much-needed, high-quality HIV care.

EPIDEMIOLOGY

As of 2009, 33.3 million people are living with HIV worldwide, with 68% (22.4 million) living in sub-Saharan Africa (WHO, 2013). The incidence of new HIV infections was 2.6 million. Unfortunately, only 36% of people indicated for treatment living in low- and middle-income countries are receiving ART. Because only 53% of pregnant women living with HIV in low- and middle-income countries were receiving ART for prevention of mother-to-child transmission (MTCT), there were 2.3 million children in the world living with HIV at the end of 2009. In the United States, more than 1.1 million people are living with HIV; however, 18% remain undiagnosed. One out of five people are not aware of their status, and as a result continue to transmit HIV to others.

There are three modes of transmission: sexual (horizontal), parenteral (blood exposure), and perinatal (vertical). Sexual transmission accounts for the majority of new infections in the United States despite the widespread encouragement of barrier contraceptives and male circumcision that can decrease the risk. With the advent of needle-exchange programs and awareness, intravenous drug users (IDUs) only account for 8% of new HIV infections in 2010 (Centers for Disease Control and Prevention [CDC], 2012). Perinatal transmission can be as high as 25% in the absence of ART. However, due to the widespread implementation of protocols for prevention of MTCT, transmission rates have decreased to <2% and fewer than 200 infants are born infected yearly in the United States (Panel, 2012). Trends of HIV transmission have evolved over the years. As of 2010, 63% of new infections were from men who have sex with men (MSM) transmission and 25% were from heterosexual transmission (CDC, 2012). There is also a disparity in new HIV infections by gender and race. Rates of new infections are highest in the Black male population, followed by Hispanic males, and Black females. Multifactorial socioeconomic influences, especially poverty, have had a large impact on disease transmission, treatment, and survival.

PHYSIOLOGY AND PATHOLOGY

The pathophysiology of HIV disease is complex, but an understanding of the viral life cycle and clinical progression of disease is necessary for optimal treatment management. Multiple sites in the life cycle of the virus must be targeted simultaneously to provide the maximum efficacy of viral suppression (Figure 37.1). HIV first binds to the CD4 cells by binding to the glycoprotein 120 (gp120). Once bound to gp120, the virus binds to a coreceptor in order to enter the cell, either CCR5 or CXCR4, although some viruses are capable of using both (dual-mixed). After HIV is attached to gp120 and a coreceptor, fusion occurs. Once inside the CD4 cell, the viral capsid uncoats for replication. HIV comes equipped with a reverse transcriptase enzyme that uses different nucleotides to synthesize RNA into double-stranded DNA. The DNA then migrates into the nucleus and is integrated into the host cell (human) DNA by the integrase enzyme. Once integrated, HIV infection is established. After integration, new virion particles and HIV proteins assemble and form a new capsid. This virion package buds through the plasma membrane and maturation begins. The protease enzyme cleaves the immature virions into functional proteins to produce a complete virus. Without protealytic cleavage, the virions are immature and noninfectious.

FIGURE 37.1
The HIV life cycle and targets for antiretrovirals.

Antiretroviral drugs have been developed to target these different steps of the life cycle. The fusion inhibitor and CCR5 inhibitors prevent HIV from entering the CD4 cell. Nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) both inhibit reverse transcription from occurring, albeit by different mechanisms. Integrase strand transfer inhibitors (INSTIs) prevent integration of HIV into the host genome, and protease inhibitors (PIs) prevent the maturation of virus, rendering the immature virions nonfunctional. A total of 27 antiretrovirals have been approved by the Food and Drug Administration (FDA); however, this chapter focuses on the agents most commonly used in clinical practice.

HIV TESTING AND INITIAL HISTORY

Patients with HIV entering into your care may be newly diagnosed or experienced with treatment. As a primary care provider, it is pertinent to implement routine HIV testing into your practice. CDC guidelines for HIV testing (Branson et al., 2006) recommend routine screening for patients aged 13 to 64 years in all health care settings after the patient is notified that testing will be performed. The patient may decline and opt out of the screening. It should be noted, however, that a separate written consent for HIV testing is not required; general consent for routine medical care should be considered sufficient consent for HIV testing. In addition, those individuals at high risk for HIV infection should be screened at least annually. High-risk individuals are those who have had unprotected sex with multiple or anonymous partners, have a history of sexually transmitted diseases, or share needles/syringes for injecting drugs. All pregnant women should have HIV testing included in their routine prenatal care, as well as a second HIV test during the third trimester to rule out false negatives, as antibody seroconversion may take up to 6 months.

Rapid HIV testing has become popular in health care settings, as the results of rapid tests performed at the point of care are available within 20 minutes. Some rapid tests are not available at point of care and must be performed in laboratories; thus, results are available within 1 hour. Several rapid tests for HIV (Clearview HIV 1/2 STAT-PAK Assay and Clearview Complete HIV 1/2, Inverness Medical Innovations; Multispot HIV-1/HIV-2 Rapid Test, Bio-Rad Laboratories; OraQuick Advance Rapid HIV-1/2 Antibody Test, OraSure Technologies; Reveal G3 Rapid HIV-1 Antibody Test, MedMira; Uni-Gold Recombigen HIV Test, Trinity BioTech) have been approved for detection of HIV antibodies by the U.S. FDA. All FDA-approved rapid antibody tests are highly sensitive and specific, and just as accurate as the standard enzyme-linked immunosorbent assay (ELISA). Positive results from both rapid testing and ELISA methods are considered preliminary and must be confirmed by either Western blot or immunofluorescence assay (IFA). The Multispot rapid test has the ability to differentiate between HIV-1 and HIV-2; however, there is no confirmatory test available for HIV-2 and providers are encouraged to contact their state health departments for diagnosis of these cases. HIV-2 may be suspected in persons of West African origin and can also cause AIDS.

In 2012, the first at-home oral HIV test was FDA approved and is available over the counter (OTC) and can be purchased online. The OraQuick home test has 99.9% specificity and 91.7% sensitivity (lower than clinic point-of-care test sensitivity to account for consumer error). As home testing provides privacy, it is possible that consumers may enter into primary care with a positive HIV test result requiring confirmation of test results. The OraQuick home test has a 24-hour, 7-days-a-week bilingual support center available for counseling and follow-up information; however, primary care providers should be well versed in educating on next steps for confirmatory testing and the importance of entering into appropriate care.

PATIENT HISTORY

Obtaining a complete history on an HIV-positive patient is extremely important to determine status of disease, comorbidities, and emotional status, and to develop a trusting relationship for providing care. The initial evaluation should include a discussion on the benefits of ART for improved survival and prevention of transmission to others. If the patient is treatment experienced, a thorough ART history is important, including drug-resistance test results if available. Table 37.1 lists suggested topics, questions, and laboratory results to obtain upon initial visit. Because patients living with HIV often live with additional comorbid conditions, it is also necessary to assess other disease states as well during the initial visit. In addition, other screening tests for sexually transmitted infections and tests to rule out opportunistic infections (OIs) are recommended in the setting of HIV primary care.

It is important for the primary care provider to obtain the patient’s complete history by asking questions in a nonjudgmental manner, especially when referring to sexual and drug history. The provider may also take the opportunity during the initial visit to introduce the importance of safe sex practices to reduce the risk of transmission, “superinfection,” and other sexually transmitted infections (Aberg et al., 2009).

After all baseline laboratory tests have been obtained, the patient should return quickly for follow-up to determine the best course of treatment. Resistance test results are valuable to help design an ART regimen, even if patients are treatment naïve. In the United States, up to 16% of new infections are transmitted by a resistant virus. Because the genotype assay is qualitative and more sensitive for detecting mixed wild-type and resistant virus, it is preferred at baseline over phenotype assay. The phenotype assays, which are quantitative, are preferred in treatment-experienced patients when complex drug-resistance mutation patterns are suspected. The HLA-B*5701 test is recommended when a patient has signs of renal impairment, in preparation for use of abacavir, which is the only NRTI not renally eliminated. HLA-B*5701 positive persons may have a severe hypersensitivity reaction to abacavir; therefore, it is recommended to obtain test results prior to abacavir use in order to avoid this potential reaction.

ACUTE HIV INFECTION

Although a patient may present at any point during the disease, the first exposure to HIV infection typically manifests as a flu-like syndrome. Approximately 40% to 90% of patients acutely infected will have some or all of the typical signs and symptoms, such as headache, fever, rash, and myalgias (Table 37.2). This viral syndrome lasts several days and then resolves spontaneously. Because these acute retroviral syndrome (ARS) symptoms are nonspecific and often resemble other self-limiting viral infections, many primary care providers may not recognize acute HIV infection.

During ARS, viral replication is at its peak and can be highly infectious. Subsequently, the host immune response mounts and the viral load decreases and symptoms resolve. The viral load stabilizes at its “set point,” with higher set points correlating to faster disease progression. Although the HIV-infected person will enter an asymptomatic clinically latent period, this does not equate to a virologically latent period. Rather, HIV replication is continuous, producing up to 10 billion viruses per day. The infected person may remain asymptomatic despite the steady destruction of CD4 cells, until the CD4 count decreases below 200 and OIs may present.

TABLE 37.1

Initial Visit

CATEGORY	EXAMPLES OF QUESTIONS	INITIAL LABORATORY TESTS
HIV testing	When was your first HIV-positive test? When was your last negative result?	Confirmatory HIV test Plasma HIV RNA (viral load)
Status of disease	When was your last HIV care visit? What is your current CD4 (T-cell) count? Do you know your lowest CD4 count? What is your current viral load? Have you ever participated in any research studies? Which ones? Have you ever had an opportunistic infection (PCP, MAC, crypto-coccal meningitis, CMV, toxoplasmosis)? When? When was your last TB test? Have you ever had TB? When?	CD4 count and percentage Genotypic resistance testing at entry into care (see below for patients already on treatment) TB test (IGRA or TB skin test)
ART history	Are you currently taking HIV medications? Can you describe the medications and how you take them? How many doses have you missed in the past week? Month? Are you experiencing any side effects? Do you know what HIV medications you have taken in the past? Do you know why they were stopped? Do you know what your CD4 and viral load were while taking your medications? Do you have any medication allergies?	Past genotype or phenotypic resistance test results, if available If VL is not controlled and >500–1,000 copies/mL, obtain genotype or phenotype resistance test CBC, BMP, LFTs, urinalysis HLA B*5701 testing (if evidence of CKD)
Other disease states	What other chronic conditions do you have? What medications are you taking, if any? What herbals or over-the-counter medications are you taking, if any? Have you had any hospitalizations or surgeries? For what reason? Have you ever had hepatitis? What type? What vaccinations have you received?	Fasting lipid panel Fasting glucose Past medical records if available Serologies for hepatitis A, B, and C viruses Screening for other sexually transmitted infections (syphilis, gonorrhea, chlamydia)
Routine care (females)	When was your last cervical Papanicolaou (Pap) test? Have you ever had an abnormal result? When was your last mammogram? How many pregnancies have you had? How many children do you have? What is their HIV status? Do you plan on having more children?	Past medical records if available
Routine care (males)	When was your last anal Pap test? Have you ever had an abnormal result? Have you ever had anal warts?	Past medical records if available
Routine care (all)	When was your last colonoscopy? When was your last vision examination? When was your last oral health examination? When was your last influenza and pneumococcal vaccination?	Past medical records if available
Family history	What health conditions run in your family? (including mental health)
Social history	What is your relationship status? Sexuality? Condom use? Who knows about your HIV status? Do you have a support system? Are you currently employed? Have you ever been incarcerated? When? Do you use tobacco, alcohol, or illicit drugs? How do you perceive your mental health? Have you ever been evaluated by a mental health provider?

ART; antiretroviral treatment; BMP, basal metabolic panel; CKD, chronic kidney disease; CMV, cytomegalovirus; HIV, human immunodeficiency virus; IGRA, interferon gamma release assay; LFT, liver function tests; MAC, Mycobacterium avium complex; PCP, Pneumocystis pneumonia

TABLE 37.2

Acute Retroviral Syndrome: Symptoms and Signs

Symptoms

Sore throat

Fatigue

Myalgias or arthralgias

Headache

Diarrhea

Weight loss

Signs

Lymphadenopathy

Fever

Night sweats

Rash

Erythematous maculopapular lesions on trunk, sometimes on extremities including palms and soles

Mucocutaneous ulceration involving mouth, esophagus, or genitals

Elevated hepatic enzymes

Neurologic symptoms

Aseptic meningitis or meningoencephalitis

Source: Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents (2013).

After ARS subsides, the following six months of HIV infection are considered “early HIV infection” or “acute infection” (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents, 2013). Based on recent literature, current guidelines recommend that ART be recommended during early HIV infection to decrease the severity of acute disease, lower the viral set point, reduce the size of the viral reservoir, and preserve immune function. There is, however, a lack of data to confirm that treatment during acute infection will result in long-term clinical benefits. Several studies that are currently ongoing will continue to evaluate the outcomes of this approach.

INITIATING TREATMENT

There are four treatment goals of ART: to (1) decrease morbidity and extend the duration and quality of survival, (2) restore and preserve immune function, (3) maximally suppress viral load, and (4) prevent transmission of HIV. These treatment goals are certainly attainable provided patients remain compliant with their ART, but the question of when to begin treatment has been a debated and changing topic.

Historically, treatment was not initiated until it was deemed necessary once CD4 counts fell <200 cells/mm³, because of the disadvantages of early treatment. This view was based on two major concerns. The older antiretrovirals had significant drug toxicities and posed concerns of long-term adverse effects. There is also the disadvantage of increased risk of antiretroviral resistance from the potential nonadherence or “pill burnout” of taking medications indefinitely. However, in recent years, studies have shown that the advantages of earlier treatment far outweigh the disadvantages.

Newer antiretrovirals do not raise the same concerns of adverse drug effects present in older treatment regimens, and studies have shown that initiating treatment earlier can decrease the risk of death and prevent transmission of HIV. For example, a large randomized controlled trial conducted in Haiti (Severe et al., 2010) established that patients who deferred ART until their CD4 counts fell below 200 cells/mm³ had a higher mortality rate (hazard ratio [HR] = 4.0; 95% confidence interval [CI]: 1.6–9.8) and a higher rate of tuberculosis (HR = 2.0, 95% CI: 1.2–3.6) when compared to patients who initiated treatment when their CD4 counts were 200 to 350 cells/mm³. Furthermore, data from several large observational studies demonstrate a higher risk of death and AIDS in patients who deferred therapy until CD4 <350 compared to those who started when their CD4 was 351 to 500 cells/mm³. Although these were observational cohort studies, all data strongly suggest that starting treatment earlier results in prolonged survival and reduces disease progression. In addition to decreasing mortality, earlier treatment has been suggested to delay, prevent, or reverse non-AIDS-defining complications such as HIV-associated nephropathy (HIVAN), liver disease, cardiovascular disease (CVD), neurologic complications, and malignancies.

Furthermore, initiating treatment quickly addresses the goal of preventing transmission of HIV. The best evidence of this phenomenon is successful prevention of MTCT. When pregnant mothers are on ART and their viral loads are undetectable, the rate of perinatal transmission decreases from 25% to <0.5%. Studies also show the efficacy of early treatment in prevention of sexual transmission. In 2011, the HIV Prevention Trials Network (HPTN) 052 Study enrolled 1,763 HIV-serodiscordant couples where the HIV-positive partner was treatment naïve with CD4 between 350 and 550 cells/mm³ (Cohen et al., 2011). Half the couples were placed in the immediate ART group and the other half in the delayed therapy group. The results demonstrated a 96% reduction in transmission associated with the immediate ART group (HR = 0.04, 95% CI: 0.01–0.27, p <.001). The striking results of this study strengthened the movement to treat HIV earlier, if only to prevent new infections from occurring. It goes without saying that all patients must be willing and able to commit to lifelong therapy and understand the importance of adherence prior to initiating ART.

As a result of the increased amount of literature supporting earlier treatment, the 2013 U.S. guidelines from the Department of Health and Human Services (DHHS) strongly recommend starting treatment when CD4 falls between 350 and 500 and moderately recommend starting treatment when CD4 >500 cells/mm³. The World Health Organization (WHO) guidelines from 2013 also recommend initiation of treatment when CD4 <500 cells/mm³and prioritize treatment in those with CD4 <350 cells/mm³ or severe/advanced HIV disease defined as WHO clinical stage 3 or 4. Both guidelines recommend initiating treatment regardless of CD4 count in individuals with active TB disease, chronic hepatitis B or C coinfection, HIVAN, and women who are pregnant and breastfeeding. Most notably, the DHHS and WHO guidelines both strongly recommend initiation of treatment in serodiscordant couples regardless of CD4 count, to prevent the risk of HIV transmission to negative partners.

ANTIRETROVIRAL THERAPY

ART requires a minimum of three active antiretroviral agents from at least two drug classes. Typically, regimens will consist of two NRTIs as the backbone with one of the following: (1) PI boosted with ritonavir, (2) NNRTI, or (3) INSTI. Other classes and combinations can be employed as optional or salvage therapy. Table 37.3 lists the current preferred initial treatment regimens and alternative combinations. These antiretroviral combinations have evidence from numerous clinical trials to demonstrate potent, durable efficacy, minimal toxicity profiles, and ease of use. Virologic efficacy in clinical trials is represented by the number of people achieving virologic suppression (undetectable viral loads). Because the virologic efficacy of these regimens is comparable, the primary care provider should consider patient-specific factors and unique characteristics of the antiretrovirals when selecting an initial regimen. Table 37.4 describes the advantages and disadvantages of the different recommended regimens. Complete dosing information is provided in Table 37.5 for all antiretrovirals; however, the text in this chapter focuses on the most commonly used and newer antiretrovirals.

TABLE 37.3

Recommended Initial Treatment Regimens

PREFERRED REGIMENS
NNRTI based PI based^a	Tenofovir/emtricitabine/efavirenz Tenofovir/emtricitabine + atazanavir/r Tenofovir/emtricitabine + darunavir/r
INSTI based	Tenofovir/emtricitabine + raltegravir Tenofovir/emtricitabine/elvitegravir/cobicistat Tenofovir/emtricitabine + dolutegravir Abacavir/lamivudine + dolutegravir
ALTERNATIVE REGIMENS
NNRTI based	Tenofovir/emtricitabine/rilpivirine Abacavir/lamivudine + efavirenz Abacavir/lamivudine + rilpivirine
PI based^a	Abacavir/lamivudine + atazanavir/r Abacavir/lamivudine + darunavir/r Abacavir/lamivudine or tenofovir/emtricitabine + fosamprenavir/r Abacavir/lamivudine or tenofovir/emtricitabine + lopinavir/r
INSTI based	Abacavir/lamivudine + raltegravir

^aRitonavir boosting is denoted by /r.

INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Source: DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents (2013).

The NRTI backbone tenofovir/emtricitabine is recommended for treatment in all treatment-naïve patients. If there is evidence of baseline renal impairment, tenofovir should be avoided, as it can cause nephrotoxicity. Hence, patients on tenofovir should have their renal function monitored by frequent serum creatinine (SCr) levels, as well as a urinalysis every 6 to 12 months, as glycosuria and proteinuria are suggestive of tenofovir nephrotoxicity. In patients who have chronic kidney disease at baseline or begin to develop acute renal insufficiency on tenofovir, the primary care provider should obtain HLA-B*5701 testing and opt to use abacavir/lamivudine instead to avoid worsening renal function. Although zidovudine/lamivudine is also an option, there are increased toxicities associated with long-term use of zidovudine. Also, zidovudine has a shorter half-life and must be dosed twice daily unless renally adjusted. Zidovudine/lamivudine is currently the recommended NRTI backbone to use in pregnancy because of ample safety and efficacy data. Due to the increased gastrointestinal (GI) adverse effects, however, many pregnant women are unable to tolerate it, and have alternatively used tenofovir/emtricitabine safely and effectively.

All the NRTIs, with the exception of abacavir, are excreted renally and doses are recommended to be adjusted according to varying estimated creatinine clearances (CrCl) to avoid drug toxicities. However, there is little evidence that these reduced doses will maintain virologic suppression and decrease toxicities. Nonetheless, all drug information databases will have renal dose adjustments recommended for the renally excreted NRTIs. The guidelines for the management of chronic kidney disease (CKD) in HIV published by the Infectious Diseases Society of America support the clinical practice of being lenient on adjusting lamivudine doses in renal impairment for two main reasons: the lack of clinical toxicity when using normal doses and to promote adherence (Gupta et al., 2005). To administer doses of lamivudine below 100 mg, an oral solution must be used, which may hinder adherence. In addition, because lamivudine is available in combination with abacavir that does not require renal adjustment and zidovudine, which only requires renal adjustment when CrCl <15 mL/min, it is more convenient for patients to use combination tablets if possible. If NRTIs are used in hemodialysis patients, they should be administered after dialysis sessions at their respective doses.

Patients who develop the M184V mutation may require an additional NRTI, as this mutation renders emtricitabine and lamivudine ineffective and decreases activity of abacavir. Instead, the mutated virus will be hypersusceptible to tenofovir and zidovudine, which therefore should be used in the regimen if possible. The M184V mutation may explain why some treatment-experienced patients have three NRTIs in their ART regimen instead of two. The specifics of all other NRTI mutations are beyond the scope of this primary care chapter; details can be found through the International Antiviral Society-USA (IAS-USA) resistance updates at www.iasusa.org/sites/default/files/tam/21-1-6.pdf

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