CLINICAL MANIFESTATIONS AND TREATMENT OF HIV AND AIDS

The course between infection with HIV and the development of full-blown AIDS can be steep or gradual and may take as long as a decade or more. If the infection is untreated, the average time from HIV infection to a diagnosis of AIDS can be 8 to 10 years. However, early detection and appropriate medical treatment may extend the lives of those infected and reduce the rates of HIV transmission (Sax & Wood, 2019).

Stages of HIV Infection and Clinical Manifestations

Without treatment, HIV infection advances in stages, progressively worsening over time. There are three stages of HIV infection, each with unique manifestations.

STAGE 1: ACUTE HIV INFECTION

Acute HIV infection is the earliest stage and generally develops within 2 to 4 weeks following infection. During this phase of the HIV infection, large amounts of HIV are being produced, there is a reduction in the CD4⁺ T cell count, and seroconversion takes place. Seroconversion is the transition from infection with HIV to the detectable presence of HIV antibodies in the blood. When seroconversion occurs, the results of an HIV antibody test change from HIV negative to HIV positive. When people have an acute HIV infection, they have a large amount of virus in their blood and are very contagious; however, they are often unaware that they are infected because they may not feel sick at all.

Eventually, this process stabilizes, and the person’s immune response begins to bring the amount of virus in the body back down to a stable level. The CD4⁺ T cell count then begins to rise, although it may not return to its levels before the infection.

During this stage people may experience a flu-like illness, which can last for a few weeks. Symptoms may be very mild and hardly noticed, and up to 60% of people with early HIV infection will be asymptomatic. The constellation of symptoms is referred to as acute retroviral syndrome. The most common findings include:

• Constitutional symptoms, which are seen in a vast majority of symptomatic patients, include fever (100.4 °F to 104 °F), fatigue, and myalgias/arthralgias.
• Neurologically, a frequent complaint is a headache often described a retroorbital pain exacerbated by eye movement. A more severe and unusual manifestation is a syndrome recognized as aseptic meningitis with severe headache, signs of meningitis, photophobia, and abnormal findings on cerebrospinal fluid analysis.
• Skin rash (generalized macular or maculopapular) occurring 48 to 72 hours after the onset of fever and persisting for 5 to 8 days may be seen most often on the upper thorax, collar region, and face but can also involve the scalp and extremities.
• Oropharyngeal symptoms are frequently seen, including sore throat with pharyngeal edema and hyperemia.
• Painful mucocutaneous ulcerations, one of the most distinctive manifestations of acute infection, may be found in the mouth, anus, penis, or esophagus.
• Nontender lymphadenopathy that primarily involves axillary, cervical and occipital nodes may develop during the second week of the illness. Mild hepatosplenomegaly may also occur.
• Gastrointestinal symptoms are common and include nausea, diarrhea, anorexia, and weight loss. More serious problems include pancreatitis and hepatitis.
• Respiratory complaints, other than cough, are uncommon during this stage and only rare instances of pneumonitis of unknown etiology with cough, dyspnea, and hypoxia.
  (USDHHS, 2020; Sax, 2019b)

STAGE 2: CLINICAL LATENCY (CHRONIC HIV INFECTION)

Following acute infection when the body loses the battle with HIV, the symptoms go away and the person will move into the second stage, referred to as the chronic infection or clinical latency phase. During this phase the virus continues to multiply at very low levels, there is a steady decline in the CD4⁺ cell count, and immunosuppression gradually develops.

People in this stage may not feel sick or have any symptoms. Without antiretroviral therapy, people can remain in this stage for 10 or 15 years, but some will move through it more quickly. Most people have few to no symptoms prior to the development of severe immunosuppression. During this stage the person can also transmit the virus to others.

Some patients with chronic HIV infection develop other comorbidities at younger ages as compared to uninfected persons, which is believed to be due to chronic inflammation and immune system activation. These comorbidities may include cardiovascular disease, osteoporosis, cognitive dysfunction, and certain malignancies (HIV.gov, 2019a; USDHHS, 2020).

STAGE 3: AIDS

AIDS (acquired immunodeficiency syndrome) is the final, severe stage of HIV infection. At this point HIV has severely damaged the immune system, and certain “opportunistic” infections or cancers that normally do not cause illness in a person with a healthy immune system begin to appear. People are diagnosed with AIDS when their CD4⁺ cell count drops below 200 cell/mm³ or when they begin to develop these opportunistic infections or cancers. As a result of improved antiviral treatment, most people with HIV in the United States today do not develop AIDS.

Once a person is diagnosed with AIDS, they have a high viral load and can transmit the virus easily to others. Without treatment, people with AIDS typically survive about three years (USDHHS, 2020). With serious opportunistic infection and without treatment, however, life expectancy is reduced to about one year (CDC, 2020a).

Signs and symptoms of some of opportunistic infections and cancers include:

• Generalized lymphadenopathy found on physical exam; nodes are mostly symmetrical, moderately enlarged, mobile, painless, rubbery, and located in the cervical, submandibular, occipital, and axillary chains
• Invasive cervical cancer with metastasis
• Candidiasis of the bronchi, trachea, esophagus, mouth, and vagina; and hairy leukoplakia (irregular white patches that may look like hair) on the tongue
• Seborrheic dermatitis and bacterial folliculitis
• Shingles (herpes zoster), a painful rash on one side of the face or body due to reactivation of the virus in a person with a past history of chickenpox
• Coccidioidomycosis, a commonly acquired fungal infection prevalent in hot, dry regions and that can cause pneumonia
• Cryptococcosis, a fungus that enters through the lungs that causes pneumonia and can spread to the brain, causing swelling
• Cryptosporidiosis, a diarrheal disease that causes abdominal cramps and severe, chronic watery diarrhea
• Cytomegalovirus, a common herpes virus, that is transmitted in body fluids such as saliva, blood, urine, semen, and breast milk and that causes diseases affecting many parts of the body, resulting in pneumonia, gastroenteritis, encephalitis, and retinitis leading to blindness if not treated immediately
• Histoplasmosis, a fungal infection that causes symptoms similar to influenza or pneumonia
• Isosporiasis, a parasite that enters the body through contaminated food or water and that causes diarrhea, fever, headache, abdominal pain, vomiting, and weight loss
• Kaposi’s sarcoma, a cancer that causes capillaries throughout the body to grow abnormally and appears as firm pink or purple raised or flat spots on the skin; it is life-threatening when it infects internal organs such as the lung, lymph nodes, or intestines
• Lymphomas, such as Hodgkin lymphoma, of the lymph nodes and other lymphoid tissue in the body, such as the bone marrow, spleen, tonsils, adenoids, and thymus
• Mycobacterium avium complex (MAC) or M. kansasii infections
• Pneumocystis jirovecii (formerly Pneumocystis carinii pneumonia), a fungal lung infection that causes difficulty breathing, high fever, and dry cough
• Progressive multifocal leukoencephalopathy, a brain and spinal cord disease that causes loss of muscle control, paralysis, blindness, speech problems, and altered mental state; progresses rapidly and may be fatal
• Recurrent pneumonias most commonly caused by Streptococcus pneumoniae
• Tuberculosis (TB), which is the most common opportunistic infection in resource-limited countries and the leading cause of death among people with AIDS; can manifest with cough, fatigue, weight loss, fever, and night sweats; can occur in the lungs as well as other parts of the body, including the larynx, lymph nodes, brain, kidney, or bones
• Wasting syndrome, the involuntary loss of more than 10% of body muscle weight while having had diarrhea or weakness and fever for more than 30 days
  (CDC, 2019l)

Other complications resulting from HIV infection can include:

• HIV-associated neurocognitive disorders (HAND) can range from mild symptoms of behavioral changes and reduced mental functioning to severe dementia causing weakness and inability to function.
• HIV-associated nephropathy (HIVAN) causes progressive acute renal failure due to direct HIV infection of renal epithelial cells and is closely associated with individuals of African descent (96% to 100%).
• Liver diseases are becoming increasingly significant sources of morbidity and mortality in HIV-infected patients, especially in those who also have hepatitis B or hepatitis C infection, and are the leading causes of non-AIDS-related death in those with HIV.
  (Sax & Wood, 2019; Mayo Clinic, 2020; Kasper & Sterling, 2017)

Less commonly, people with HIV/AIDS may develop the following cancers:

• Angiosarcoma, which begins in the lining of the blood vessels
• Anal cancer
• Liver cancer
• Mouth and throat cancers
• Lung cancer
• Testicular cancer
• Penile cancer
• Colorectal cancer
• Skin cancers, including basal cell carcinoma, squamous cell carcinoma, and melanoma
  (ASCO, 2019)

CLINICAL STAGES OF HIV INFECTION

Stage	Description
Stage 1: Acute HIV infection	Occurs within 2–4 weeks after infection Symptoms similar to the flu Large amounts of virus produced Seroconversion occurs with detectable antibodies within 3 weeks in majority of infected people Body brings virus back down to low levels
Stage 2: Clinical latency (chronic HIV infection)	Virus continues to multiply at very low levels Asymptomatic or only mild symptoms Can extend for 10 or 15 years Associated with high levels of inflammation and comorbidities
Stage 3: AIDS	Immune system is severely damaged CD4+ cell count drops below 200 cells/mm3 Development of opportunistic infections Development of various types of cancers Development of neurocognitive disorders Development of nephropathy or liver diseases

Patient Management and Care

Optimal care of people with HIV/AIDS includes antiviral therapies, health maintenance, and referral to support services in addition to an emphasis on prevention of transmission to uninfected partners.

HIV/AIDS SELF-MANAGEMENT

Those with HIV/AIDS require medical intervention as well as behavioral interventions. The Institute for Healthcare Improvement (IHI, 2020) notes that it is extremely important that patients with HIV/AIDS play a major role in managing their own condition. Each patient has unique desired outcomes and needs that require appropriate interventions. Each patient should be given basic information about HIV/AIDS and its treatment; assistance with self-management skill building; and ongoing support from the healthcare team, family, friends, and community.

The IHI recommends that self-management include:

• Collaborative goal setting
• Monitoring of symptoms
• Lifestyle modifications to improve overall health and well-being, such as healthy diet, regular exercise, and smoking cessation
• Strict adherence to prescribed dosage and frequency of antiretroviral medications
• Good communication with the healthcare team, family members, and others
• Involvement in ongoing problem-solving to overcome potential barriers

Patients with HIV are faced with many emotional and physical challenges because of the disease and warrant sensitivity by the healthcare team to assist in dealing with them. Evidence-based techniques should be utilized to emphasize patient empowerment, collaborative goal setting, and problem-solving to help reduce barriers to self-management activities.

CASE MANAGEMENT

Case management is a formal and professional service with the goal of linking people with chronic conditions such as HIV/AIDS and multiple service needs to primary medical healthcare, treatment, and social services, working to ensure that they receive timely, coordinated assistance to enhance their ability to function independently. The overall objectives of case management are to:

• Assess and determine each person’s needs as well as related strengths and challenges
• Develop and implement a service plan that builds on those strengths and overcomes those challenges
• Assist patients to gain and maintain access and adherence to medical care and treatment
• Provide linkage to the continuum of resources and services aimed at assisting the patient to achieve and maintain stability across many life domains
• Promote knowledge and skill-building to enhance patients’ confidence in caring for their disease and the many systems involved in their disease management
• Promote viral suppression for the purpose of reducing transmission of HIV

Antiretroviral Therapy (ART)

Antiretroviral therapy is the daily use of a combination of medications to treat HIV. ART does not cure HIV but transforms it into a manageable chronic condition and has led to dramatic decreases in morbidity and mortality. These medications:

• Reduce the amount of HIV in the body
• Reduce the risk of HIV transmission
• Prevent HIV from advancing to AIDS
• Protect the immune system

ART is recommended to be offered to all HIV-infected patients, including infants and children, including asymptomatic individuals, regardless of their immune status. For most patients, ART should be initiated soon after an initial diagnosis is made. Initiating ART at the first visit improves outcomes and adherence to care (USDHHS, 2020).

TYPES OF ANTIRETROVIRAL MEDICATIONS

There are seven drug classes of antiretroviral medications whose actions are based on the following seven-step life cycle of HIV, as described in the table below:

CLASSES OF ANTIRETROVIRAL MEDICATIONS

Step in HIV Life Cycle	Medications Acting on That Step
1. Binding to receptors on the CD4+ T cell	CCRS antagonists, post-attachment inhibitors
2. Fusion of the HIV and CD4+ T cell	Fusion inhibitors
3. Reverse transcription to convert HIV RNA into HIV DNA, which migrates into the nucleus of the cell	Non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors
4. Integration or insertion of HIV DNA into the CD4+ T cell DNA in the nucleus	Integrase inhibitors
5. Replication by the HIV-infected cell DNA of HIV building blocks	No medications available that act on this step
6. Assembly of new HIV building blocks into immature HIV	No medications available that act on this step
7. Budding and maturation	Protease inhibitors

For most people, an ART regimen consists of a combination of these various classes of medications.

ART MEDICATIONS

Drug Class	Generic Name (Brand Name)
(USDHHS, 2020; Fletcher, 2018)
Nucleoside reverse transcriptase inhibitors (NRTIs): inhibit transcription of viral RNA into DNA	Abacavir (Ziagen) Emtricitabine (Emtriva) Lamivudine (Epivir) Tenofovir disoproxil fumerate (Viread) Zidovudine (Retrovir)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs): inhibit transcription of viral RNA into DNA	Doravirine (Pifeltro) Efavirenz (Sustiva) Etravirine (Intelence) Nevirapine (Viramune, Viramune XR) Rilpivirine (Edurant)
Protease inhibitors (PIs): inhibit the final step of budding and maturation	Atazanavir (Reyataz) Darunavir (Prezista) Fosamprenavir (Lexiva) Ritonavir (Norvir) Saquinavir (Invirase) Tipranavir (Apitvus)
Fusion inhibitors (FIs): inhibit the binding and fusion with a CD4+ cell	Enfuvirtide (Fuzeon)
Integrase strand transfer inhibitors (INSTIs): inhibit the process of insertion of HIV DNA into the cell	Dolutegravir (Tivicay) Raltegravir (Isentress, Isentress HD)
Chemokine receptor antagonists (CCR5 antagonists): inhibit binding and fusion	Maraviroc (Selzentry)
Entry inhibitors (CD4-directed post-attachment inhibitors): block HIV from attaching to the cell’s coreceptors and entering the cell	Ibalizumab-uiyk (Trogarzo)

These medications are also found in combination forms that include two or more of the HIV medications from one or more drug classes (e.g., Truvada, Combivir). In addition, there are pharmacokinetic enhancers (e.g., cobicistat/Tybost) that are used to increase the effectiveness of an HIV medication (Fletcher, 2018).

ANTIRETROVIRAL THERAPY SIDE EFFECTS

Today’s HIV medications have fewer side effects, fewer people experience them, and they are less severe than in the past. Side effects can differ from person to person and depend on the type of medication. Some side effects can occur at the start of taking a medication and may last only a few days or weeks, while other side effects can begin later and last longer. Some of the more common side effects of ART include:

• Loss of appetite
• Nausea and vomiting
• Diarrhea
• Sleep disturbances
• Fatigue
• Headache
• Rash
• Dizziness
• Mood changes, depression and anxiety

Other less common side effects include:

• Hypersensitivity or allergic reactions
• Bleeding
• Bone loss
• Heart disease
• Lipodystrophy (loss or gain of fat in certain body areas)
• Hyperglycemia and diabetes
• Lactic acidosis
• Kidney, liver, or pancreas damage
• Numbness, burning, or pain in hands or feet due to neurologic problems

Having other medical conditions and taking other medications may increase the risk of side effects or cause drug interactions (USDHHS, 2020).

INITIATING ART

ART should be initiated as soon as possible after a diagnosis is made. But even initiation of ART in patients who already have an acute, AIDS-associated opportunistic infection or malignancy can improve immune function and potentially enhance the successful treatment of the infection.

Because of metabolic disorders that can occur in HIV-infected patients, lipid and fasting glucose or hemoglobin A1C levels should be drawn to establish a baseline prior to initiation of ART, with more frequent monitoring warranted in patients who have abnormal results.

It is extremely important to discuss strategies for optimizing engagement in care, continuous access to ART, and adherence to the prescribed regimen. The lack of adherence or intermittent access to ART can result in treatment failure and the emergence of drug-resistant mutations that can compromise future treatment options. Drug resistance occurs more frequently in those patients who initiate therapy later in the course of HIV infection than in those who begin ART earlier.

ADHERENCE ISSUES

Several clinical, behavioral, and social factors have been associated with poor adherence. These factors include untreated major psychiatric disorders, neurocognitive impairment, substance use disorder, unstable housing, unfavorable social circumstances, patient concerns about side effects, and poor adherence to clinic visits (USDHHS, 2020; Sax, 2018).

Because some people may fail to engage in care between their initial HIV diagnosis and the time ART is prescribed, it has been proposed that rapid ART initiation on the same day that the patient receives the HIV diagnosis may increase engagement in care and reduce the time during which the person awaiting test results can transmit HIV. Studies are underway as to whether this strategy improves long-term care engagement and virologic suppression (USDHHS, 2020).

Adolescents and Adherence

Compared to adults, adolescents have shown significantly lower levels of ART adherence and viral suppression, as well as high rates of viral rebound following initial viral suppression. Recently, more adolescents have been prescribed once-daily regimens, which has increased the rate of viral suppression but has no significant impact on adherence.

Because adolescents often have psychosocial and other barriers to adherence, these should be carefully assessed when considering ART initiation. To enhance the benefit of ART for adolescents, a multidisciplinary care team should provide psychosocial and adherence support to this population (USDHHS, 2020).

Persons Who Use Substances and Adherence

When choosing ART regimens for persons who use substances such as alcohol or other drugs, clinicians must consider the potential barriers to adherence, comorbidities that could impact care (such as advanced liver disease resulting from alcohol use or hepatitis), potential drug-drug interactions, and possible adverse events associated with medications. Adherence should be discussed during multiple nonjudgmental evaluations.

For such patients, it is recommended that simplified ART regimens be considered to aid in adherence to ART. Such regimens should be simple to take (such as a once-a-day, single-tablet regimen) and have the lowest possible risk of hepatotoxicity.

Adherence counseling should emphasize the benefits of ART use and that reducing substance use may improve adherence to ART (USDHHS, 2020).

ART MONITORING

Patients who are on antiretroviral therapy require ongoing monitoring to assess for adherence and therapeutic response and to identify adverse events related to the chronic administration of these toxic medications.

Following initiation of ART, a patient follow-up within one or two weeks assesses for adverse effects and adherence. Adherence may be difficult to assess, as patients are found to often exaggerate adherence. Present-day therapies, however, are more potent, have a higher genetic barrier to resistance, and a long serum half-life, which allows for less stringent adherence compared with earlier HIV medications. Once patients are clinically stable on their ART regimen, they should be reassessed every 3 to 6 months.

Routine laboratory monitoring includes:

• Complete blood count with differential
• Blood urea nitrogen and creatinine
• Liver function tests
• Lipid and glucose levels
• Urinalysis

HIV RNA testing is done two weeks following initiation and then every 4 to 8 weeks until the viral level falls below the limit of assay detection. Thereafter, viral load is measured every 3 to 6 months to confirm ongoing viral suppression. A CD4⁺ T cell count should be obtained 3 months after initiating ART and every 3 to 6 months thereafter (Sax, 2018).

ART COMPLICATIONS

Adverse effects have been reported with all antiretroviral drugs, but newer regimens are associated with few serious and intolerable effects. The focus of patient management today is on individualized therapy to avoid long-term adverse effects. There are several factors that predispose patients to adverse effects, including:

• Concomitant use of medications with overlapping and additive toxicities
• Comorbid conditions that increase the risk of or exacerbate adverse effects, such as alcoholism or viral hepatitis
• Borderline or mild renal dysfunction, which increases risk of nephrotoxicity
• Drug-drug interactions
• Genetic factors that predispose patients to hypersensitivity reaction, neuropsychiatric toxicity QT interval prolongation, or hyperbilirubinemia

ART-associated adverse effects range from acute and potentially life-threatening to chronic and insidious. Common and/or serious adverse effects include:

• Bleeding events
• Bone marrow suppression
• Calculi (nephrolithiasis and cholelithiasis)
• Cardiac events (e.g., myocardial infarction, stroke)
• Decreases in bone mineral density
• Diabetes mellitus/insulin resistance
• Dyslipidemia
• Gastrointestinal effects (e.g., nausea, diarrhea)
• Hepatic effects
• Hypersensitivity reaction
• Insulin resistance
• Icterus (jaundice)
• Lactic acidosis
• Lipodystrophy
• Neuropsychiatric issues (e.g., suicidal ideation, depression, ataxia, encephalopathy)
• Rash
• Renal effects
  (USDHHS, 2020)

INDICATIONS FOR CHANGING MEDICATIONS

On occasion, assessments find that the current regimen requires changing. Common reasons for changing the regimen include:

• Failure of the medication(s) to suppress viral load
• Adverse effects related to toxicity
• Intolerance to the medications
• Inconvenience or preference, such as frequency of dosing, pill burden, requirements for co-administration with food
  (Sax, 2018)

DRUG RESISTANCE

HIV drug resistance is caused by mutations to the virus’s genetic structure that are slightly different from the original virus. As the virus multiplies in the body, it sometimes mutates. This can occur while a patient is taking HIV medications, leading to the development of drug-resistant HIV. Once drug resistance develops, the medications that controlled a patient’s HIV are no longer effective. HIV treatment failure results, and the person can transmit the virus to another individual, who will than have reduced treatments available.

Drug-resistance testing is done after HIV is diagnosed but before the person starts taking HIV medications. Drug resistance testing results help determine which HIV medications are or are not to be included in the patient’s first HIV regimen.

Once HIV treatment is started, a viral load test is used to monitor whether the medications are controlling the patient’s HIV. If testing indicates that the person’s HIV regimen is not effective, drug-resistance testing is repeated. These test results can identify whether drug resistance is the problem, and if so, they can be used to select a new regimen (USDHHS, 2020).

ART AND ALTERNATIVE AND COMPLEMENTARY THERAPIES

In addition to the medical care patients with HIV infection receive from their providers, many use alternative and/or complementary therapies to improve their immune systems and to address symptoms and/or side effects from the medications taken to treat HIV. Many people report positive results from using alternative therapies; however, there is not enough research on their effectiveness. Some common therapies include:

• Yoga
• Massage
• Acupuncture
• Aromatherapy
• Relaxation techniques (e.g., meditation, visualization)
• Herbal medicines
  (VA, 2019)

(Caution: St. John’s wort interacts with the liver and can alter the action of some HIV-medications.)

Managing Coexisting Infections

Infections that are commonly found in patients who are HIV-positive include a number of other STIs, tuberculosis, and hepatitis. Coexisting infections may increase the risk of transmission of HIV and make its treatment more complex.

TUBERCULOSIS

Tuberculosis (TB) is an opportunistic infection that often occurs in people with weakened immune systems. When HIV weakens the immune system, the risk for contracting tuberculosis increases. Worldwide, TB is one of the leading causes of death among people with HIV. In the United States, where HIV medications are widely used, fewer people with HIV contract tuberculosis. TB, however, still affects many people in this country, especially those who were born outside the United States.

Tuberculosis is an airborne disease that usually affects the lungs, but the bacteria can attack any part of the body and, if untreated, cause death. Once in the body, the bacteria remain inactive or become active. Inactive TB is referred to as “latent” and TB disease as “active.”

In those with latent TB, the bacteria do not grow and do not result in any symptoms. During the latent period, TB cannot be transmitted to others. Latent TB is more likely to advance to active tuberculosis in people with HIV and may cause HIV to worsen. With active TB disease, the bacteria are growing and lead to having symptoms. It is during this period that bacteria can be spread to others.

The clinical manifestations of tuberculosis in HIV-infected persons are influenced by the degree of immunosuppression and can include:

• Persistent cough with hemoptysis
• Chest pain
• Fatigue
• Loss of appetite
• Weight loss
• Fever
• Night sweats

HIV-infected patients with advanced immunosuppression are at increased risk for extra-pulmonary TB and disseminated TB, with virtually any site in the body being involved. Disseminated TB can present as an acute fulminant illness (TB septic shock) in patients who are also infected with HIV, which can result in death. In contrast, active TB may be subclinical in some patients with advanced immunosuppression with no symptoms and a normal chest X-ray (Libman & Pollack, 2020; Pozniak, 2019).

Patients with HIV/TB coinfection are treated for both diseases. Studies have shown that starting antiretroviral therapy early (e.g., within 4 weeks after the start of TB treatment) reduces progression to AIDS and death. Some patients with coexisting HIV and TB infection, however, may develop a paradoxical response (immune reconstitution inflammatory syndrome [IRIS]) when starting antiretroviral therapy. This response has been attributed to a stronger immune response to the tuberculosis bacteria, resulting in fever, worsening pulmonary infiltrates, and lymphadenopathy (Herchline, 2020).

Tuberculosis Treatment

In general, tuberculosis treatment is the same for people with and without HIV. TB medications are used to prevent latent TB from advancing to active TB and to treat TB diseases. The choice of TB medicines and the length of treatment will depend on whether the patient has latent or active TB. Taking certain HIV and TB medicines at the same time can increase the risk of drug-drug interactions and side effects (Libman & Pollack, 2020; USDHHS, 2020).

Initial treatment of TB begins with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin, and once the TB isolate is known to be fully susceptible, ethambutol or streptomycin are discontinued.

HIV-infected patients with coexisting tuberculosis should start treatment for TB as soon as possible, finish the medication regimen, and take the drugs exactly as prescribed. Drug-resistant TB can develop when a patient is not treated with the right drugs or does not take the drugs the right way. TB that is resistant to drugs is harder to treat and can lead to death.

Healthcare providers should prescribe the shortest regimens whenever possible, as patients are more likely to finish shorter treatment regimens. The most effective way to ensure that medications are being taken as prescribed is through the use of patient-centered care, which may include supervision known as “directly observed therapy” (DOT) (CDC, 2020i).

VIRAL HEPATITIS

Because hepatitis B and C infections are transmitted in the same ways as HIV, people with HIV infection in the United States are often also affected by chronic viral hepatitis. About 1 in 10 people living with HIV are coinfected with hepatitis B virus (HBV), and about 1 in 4 are coinfected with hepatitis C virus (HCV). In the United States, increases in injection behaviors have resulted in the rise of hepatitis infection and more individuals at risk for HIV/HCV coinfection.

Hepatitis progresses more quickly in those infected with HIV, causing more liver-related health problems. It is a major cause of non-AIDS-related deaths among people living with HIV. There are conflicting findings, however, as to whether HCV infection has a deleterious effect on the course of HIV infection. HCV replication may result in generalized immune activation, which is associated with shorter survival in patients with HIV.

Hepatitis B and C are both spread:

• By sharing needles, syringes, and other injection equipment
• Sexually
  • HBV is more likely than HCV to be sexually transmitted.
  • Sexual transmission of HCV is most likely to happen among gay and bisexual men who are living with HIV.
• Mother to child
  • HIC/HCV coinfection increases the risk of passing on hepatitis C to the baby.
(HIV.gov, 2019b; Libman & Pollack, 2020)

Hepatitis Treatment

HIV/HBV and HIV/HCV coinfections can be effectively treated in most people, but treatment can be complex. When patients with concomitant HCV are initiated on ART, close laboratory follow-up is necessary, and patients should be educated about symptoms that may suggest liver injury such as jaundice or darkening of urine, right upper quadrant pain, nausea, anorexia, pruritus, and fatigue.

Hepatitis B treatment can delay or limit liver damage by suppressing the virus. Like treatment for HIV, hepatitis B treatment may need to be taken for the patient’s lifetime.

Newer treatments for hepatitis C approved in recent years have few side effects and do not require injection. These treatments are able to cure more than 90% of people, including those living with HIV, in 12 to 24 weeks (HIV.gov 2019b; Libman & Pollack, 2020).

Hepatitis Prevention

Hepatitis B vaccine is the best way to prevent infection. People with HIV who do not have active HBV infection should be vaccinated. Currently there are is no vaccine for HCV, and the best way to prevent it is by always using new sterile needles or syringes for injecting drugs and to avoid reuse or sharing of needles or other drug preparation equipment (HIV.gov, 2019b).

HIV AND SEXUALLY TRANSMITTED DISEASES

HIV is an STD. Chlamydia, gonorrhea, human papillomavirus (HPV) infection, and syphilis are some examples of other STDs. Having an STD can make it easier to become infected with HIV because STDs can result in sores or breaks in the skin, which then makes it easier for HIV to enter the body. Having HIV and another STD may increase the risk of HIV transmission.

STDs caused by bacteria or parasites can be effectively cured with medications, but there is no cure for those STDs caused by viruses. Treatment, however, can relieve or eliminate symptoms and help keep the STD under control. Treatment also reduces the risk of transmitting the STD to a partner (NIH, 2020b).

Initial Evaluation of HIV-Infected Patients

Initial evaluation of the patient with HIV includes an assessment of the stage of HIV disease, risk for coinfections, identification of comorbidities associated with HIV infection or treatment, and the selection of an antiretroviral regimen.

MEDICAL HISTORY

A comprehensive medical history is obtained on initial visit with a patient who has been diagnosed with HIV and includes:

History of Infection

• Risk behaviors for HIV infection and approximate date of onset
• History of opportunistic infections
• Knowledge of initial and recent CD4⁺ T cell counts and viral load (RNA) results
• Medical records obtained to confirm treatment history and antiretroviral drug resistance

Medical History

• Coinfections with hepatitis B, hepatitis C, or tuberculosis
• History of cardiovascular risk factors or diseases
  • Hypertension
  • Diabetes mellitus
  • Dyslipidemia
• History of sexually transmitted infections
• Gynecologic and obstetrical history
• Malignancies
• Psychiatric history, particularly depression
• Other comorbidities, such as:
  • Chronic renal insufficiency
  • Peripheral neuropathy
  • Metabolic bone disease
• Medications and allergies
  • Antiretroviral drug history
• Immunization history
  • Pneumococcal
  • Tetanus toxoid
  • Hepatitis A and B
• Social history
  • Ongoing risk factors for HIV transmission
  • Other exposures that may increase risk of other infections or comorbidities
  • Substance use
  • Employment, housing, and insurance status
  • Travel history
  • Smoking history
  • Sexual history
    • Condom use
    • Contraceptive use
• Family medical history

Review of Systems (to assess for constitutional symptoms)

• Fevers
• Night sweats
• Weight loss
• Localized complaints
• HIV-related common symptoms
  • New visual floaters
  • Change in vision
  • Candidiasis (thrush)
  • Dysphagia (difficulty swallowing)
  • Odynophagia (painful swallowing)
  • Cough
  • Shortness of breath
  • Diarrhea
  • Skin rash
  • Headache
  • Inability to concentrate
  • Muscle weakness or paresthesia
(Libman & Pollack, 2020)

PHYSICAL EXAMINATION

A complete physical examination is carried out on initial evaluation, including an assessment for findings that are common in the patient with HIV, particularly those with advanced immunosuppression.

• Skin
  • Seborrheic dermatitis
  • Eosinophilic folliculitis
  • Psoriasis
  • Dermatophytosis (superficial fungal disease)
  • Molluscum contagiosum (poxvirus skin infection)
  • Herpes simplex
  • Herpes zoster (shingles)
  • Kaposi’s sarcoma
• Body fat and body fat distribution
  • Lipodystrophy
• Oral mucosa
  • Candidiasis
  • Oral hair leukoplakia
  • Herpetiform lesions (canker sores)
  • Herpes simplex (cold sores)
• Anogenital for evidence of STIs
• Neurological exam, including assessment of cognitive function
• Signs and symptoms of pneumonia
  • Fever
  • Cough
  • Dyspnea
  • Tachypnea
  • Digital clubbing
• Generalized cervical, axillary, or inguinal lymphadenopathy
  (Libman & Pollack, 2020; Rivera, 2020)

LABORATORY TESTING

Initial laboratory testing includes an assessment of the patient’s HIV status and baseline testing for organ function and potential coinfections.

HIV-specific initial laboratory testing includes:

• HIV serology
• CD4⁺ T cell count and percentage
• Viral load (RNA)
• Drug resistance testing

General blood and urine testing should include:

• Complete blood count and differential
• Renal function tests
• Hepatic function tests
• Glucose and lipid profile
• Urine pregnancy test

Screening for coinfections includes:

• Viral hepatitis
• Tuberculosis with follow-up chest X-ray for positive screening results
• STDs
  • Syphilis
  • Gonorrhea
  • Chlamydia
  • Trichomonas in women
• Latent cytomegalovirus
• Latent varicella-zoster virus
• Latent toxoplasma
• Screening for HIV-associated neoplasia
  • Cervical cancer
  • Anal cancer
• Bone marrow density testing for postmenopausal women and men aged 50 years and older
• G6PD screening for glucose-6-phosphate dehydrogenase deficiency for patients of African, Asian, or Mediterranean descent, (as certain drugs used in treatments of patients with HIV can precipitate hemolysis in those with deficiency)

Additional testing is done to evaluate for potential adverse reactions and drug activity prior to selection of appropriate antiretroviral agents (Libman & Pollack, 2020).

Ongoing Management of HIV-Infected Patients

Because of antiretroviral therapy, opportunistic infections have become less common, and patients with HIV now have a nearly normal life expectancy. The majority of infected patients die from non-AIDS-related conditions, including cardiovascular disease, renal disease, liver disease, malignancies, and other age-related illnesses. Many of these begin to develop at an earlier age than in uninfected people. In addition, there is a range of long-term complications that might occur for those individuals who in the past were treated with the older antiretroviral drugs.

It is the role of primary healthcare providers to oversee and coordinate the multidisciplinary services necessary for the best health outcomes for HIV-infected patients. Following initial evaluation, follow-up visits depend on the patient’s stage of HIV infection, the type of antiretroviral therapy the patient is taking, other comorbidities, and complications.

MONITORING FOR HEMATOLOGIC, RENAL, AND HEPATITIS TOXICITY

Because HIV is associated either directly or secondarily with comorbid conditions such as bone marrow abnormalities and kidney and liver function problems, patients require monitoring for hematologic, renal, and hepatitis toxicity. Monitoring may include:

• Complete blood count with differential every 3 to 6 months
• Basic chemistry, including BUN and creatinine 2 to 8 weeks following initiation of ART and then every 3 to 6 months
• Urinalysis following initiation of ART or change in medication, and annually following that
• Alanine (ALT), aspartate aminotransferases (AST) and total bilirubin 2 to 8 weeks following initiation of ART and then every 3 to 6 months

MANAGEMENT OF CARDIOVASCULAR RISK AND DISEASE

Following baseline screening, dyslipidemia screening is done:

• Annually if the patient is not on ART
• Prior to initiating ART
• Within 2 to 3 months following initiation of a new ART regimen and every 6 to 12 months thereafter

Preventive care involves encouraging lifestyle changes, changing ART medication regimen, or treating with statin drugs.

GLUCOSE INTOLERANCE AND DIABETES MELLITUS

Following baseline screening, monitoring of blood glucose or A1C is performed:

• Annually if not on ART
• Prior to initiating ART
• Within 1 to 3 months after starting a new ART regimen
• Every 3 to 6 months if abnormal
• If normal, every 12 months while on ART

Weight loss is encouraged through diet, exercise, and treatment with oral hypoglycemic drugs and/or insulin if necessary.

NEUROPSYCHIATRIC DISORDERS

Both psychiatric and neurocognitive problems are common among this population, and certain antiretroviral agents are associated with problematic neuropsychiatric effects if the patient has pre-existing psychiatric disorders. Patients are monitored for:

• Symptoms and signs of depression and anxiety
• Substance use
• HIV-associated neurocognitive disorder (HAND)

CHRONIC PAIN

Chronic pain is quite common among those with HIV infection, primarily pain that is neuropathic in origin. Chronic pain in individuals with HIV is strongly associated with mental illness, particularly depression and substance use. The approach to management of chronic pain begins with psychoeducation about the nature of chronic pain, and treatment options should not include the use of opioids. Instead, other modalities are employed, such as physical therapy, cognitive behavioral therapy, or supportive psychotherapy.

FATIGUE

Fatigue is a common, often persistent symptom among individuals with HIV infection. Physiological factors associated with fatigue or the severity of fatigue in HIV-infected patients include liver disease, hypothyroidism, hypogonadism, anemia, and duration of HIV infection. Fatigue interferes with physical, social, and mental functioning, and may also interfere with adherence to ART.

Complaints of fatigue require searching for medical or psychiatric causes (especially hypogonadism), medication review, inquiry into the patient’s sleep patterns, and treatment of the underlying cause, when found. Testosterone may help hypogonadal men with fatigue, and moderate exercise is an option for others.

PREVENTION AND LIFESTYLE CHANGES

At each visit patients should be involved in a discussion of sexual practices and prevention counseling. Annual screening for STDs is recommended for patients who are at continued risk and more often for those who are engaged in high-risk behaviors. Smoking has been found to be quite common among patients with HIV, and smoking cessation services should be offered and encouraged.

Immunizations are an important part of preventive care for those with HIV. Inactivated viruses are recommended, and certain live vaccines are considered safe. Vaccines for which HIV is an indication include:

• Pneumococcal vaccine
• Hepatitis A
• Hepatitis B
• Meningococcal vaccination
• Others if specifically indicated, including:
  • Haemophilus influenza b
  • Varicella
  • Inactivated zoster vaccine for ages 50 or older
(Hibberd, 2020; Pollack & Libman, 2019; Aberg & Cespedes, 2020)