Treatment and management of HIV infection is continually evolving. Advances in antiretroviral therapy (ART), improved prevention strategies, and changes in public health policy have transformed HIV from a terminal illness to a chronic disease. Individuals diagnosed with HIV in the current era of ART are able to live longer than those diagnosed in the early days of the epidemic.1 Diseases that were never considered part of the HIV disease spectrum, such as cardiovascular disease, diabetes, and liver disease, are surpassing opportunistic infections as the leading causes of morbidity and mortality in persons living with HIV.2-5 This shift in the disease paradigm means that more primary care providers are managing the chronic diseases in people living with HIV. It is critical that primary care nurse practitioners (NPs) be versed in the essentials of HIV care, including diagnosis, assessment, and management. This article reviews issues relevant for primary care clinicians, such as advances in HIV testing, current approaches to treatment, a review of comorbidities, and the latest information on HIV prevention strategies.
The statistics
The CDC estimates that nearly 1.2 million people are living with HIV in the United States, with approximately 40,000 to 50,000 new infections occurring annually.6 Although the number of new infections is significantly lower compared to the early years of the epidemic, the rate of new infections has remained relatively stable over the past decade.6 On a global level, HIV is a disease that primarily affects heterosexuals; however, in the United States, the disease burden remains among men who have sex with men (MSM).6,7 With regards to transmission risk, MSM accounted for 62% of new infections in 2011, and heterosexual contact/injection drug use accounted for 27% and 8% of new cases, respectively.6 In the United States, HIV has disproportionately affected communities of color. Blacks, estimated to make up approximately 13% of the general population, comprise nearly 30% of those living HIV.6 The greatest increase in incidence in the most recent years has been seen among young black MSM and black heterosexual women.6
Pathophysiology
HIV is a retrovirus that contains a single-stranded RNA.8 Its main target cell is the CD4 cell (also known as the T4 cell). As a retrovirus, HIV must undergo reverse transcription in order to replicate. Dendritic cells in the mucosal surfaces of the genital tract transport HIV into the lymphatic system, where HIV binds to CD4 cells. After HIV fuses to the CD4 cell, HIV RNA undergoes a process of reverse transcription in which the virus' RNA is transcribed to proviral DNA (see HIV replication cycle). From the proviral DNA, chains of RNA are formed. Protease enzyme cleaves the newly formed RNA into multiple RNA chains that eventually become individual virions capable of infecting new cells. Once the new virions are formed and released, the host CD4 cell is destroyed. The entire viral reproduction process is prone to replication errors. These errors in turn result in the virus' ability to mutate, which is one of the reasons why treatment of HIV was initially challenging.
Over time, the rate of HIV replication surpasses the rate of CD4 cell production, and the CD4 cell count declines, resulting in immune suppression. Individuals with severe immune suppression (CD4 count less than 200 cells/mcl) are prone to opportunistic infections, such as pneumocystisjiroveci pneumonia (PCP). Therefore, the goal of HIV treatment is to increase or maintain the CD4 cells and suppress HIV replication.
Testing and diagnosis
In 2006, the CDC issued recommendations that everyone 13 to 64 years of age-regardless of risk-be screened for HIV as part of routine healthcare.9 Pregnant women, women who live in areas where the prevalence of HIV is greater than 1.0%, or women who present in labor without evidence of a previous test should also be screened for HIV. Persons at high risk for HIV infection should be screened annually or more frequently based on individual circumstances. One of the rationales for routine screening is that previous guidelines specified screening only high-risk individuals; however, this missed a significant proportion of those infected. The CDC, therefore, has encouraged clinicians to incorporate and integrate HIV screening into routine care. The recommendations state that patients should be notified that HIV testing is included as part of regular care unless the patient chooses not to have the test done (also referred to as opt-out testing).9 The 2006 recommendation also states that oral consent for HIV testing is sufficient and that the need for written consent is not required.9 These recommendations were made to facilitate HIV testing in healthcare settings, but due to various state and institutional policies regarding HIV testing and consent, full implementation and adoption of the CDC guidelines have been met with obstacles.10
In April 2012, the U.S. Preventive Services Task Force (USPSTF) issued revised recommendations regarding HIV testing. The USPSTF now recommends that anyone 15 to 65 years of age be tested for HIV regardless of risk.11 However, this shift toward universal testing is based on review of evidence, which not only supports the benefit of early diagnosis and treatment, but the public health impact of identifying persons who may unknowingly infect others due to lack of knowing their own HIV status. The revised recommendations were given an "A" level rating, the highest level of evidence and the strongest recommendation from this expert panel of health practitioners.11
Diagnosis of HIV infection is traditionally made through the detection of HIV antibodies, but several testing modalities are available.12 The enzyme-linked immunosorbent assay (ELISA), or the enzyme immune assay (EIA), is a method that requires specimens to be sent to a lab for testing. Specimens found to be positive by ELISA/EIA need a confirmatory Western blot, which looks for specific bands associated with HIV.13
Other testing methods include point-of-care tests (also known as rapid HIV tests) that can be performed on saliva, finger stick, or blood samples.13 Rapid tests can be done in various venues, such as EDs, mobile testing centers, primary care offices, or other outpatient venues. The advantage of rapid testing is the ability to get results within 20 to 40 minutes. This allows providers the opportunity to convey the results to patients in a timely manner. However, a positive rapid test requires confirmatory testing. Western blot is currently the confirmatory test of choice; however, newer testing algorithms are being proposed and reviewed.12,14
The time period between exposure and development of detectable antibodies on ELISA, EIA, or rapid tests can vary, but most tests are able to detect antibodies within 4 to 6 weeks following infection.13 The period between infection and development of detectable antibodies is also known as the "window period."8
A fourth-generation test is also available for rapid diagnosis. This new testing methodology searches for both HIV antibodies as well as p24 antigen (an antigen associated with HIV). This combined antigen/antibody test allows for the early identification of HIV infection during the window period and may be useful when acute HIV infection is suspected.14
Direct measurement of HIV through the use of HIV RNA viral load testing is typically used for monitoring the disease. However, in cases of suspected acute HIV infection, the HIV RNA viral load test can be used.15,16 Since there is a delay between infection and the development of antibodies, direct measurement of HIV viral load is a way to identify persons who may be in the window period. HIV viral load testing for routine screening is not recommended.15
In July 2012, the U.S. FDA approved a home HIV test kit.17 The test kit is available over-the-counter without a prescription and uses the same technology as the rapid point-of-care tests used in healthcare facilities. There has been discussion over the benefits of home testing, and some state that home testing may not necessarily increase the number of individuals who are tested and express concern that those who test positive may not receive appropriate posttest counseling.18
Acute HIV infection
Acute HIV infection refers to the first few weeks following infection with HIV and is often characterized by a constellation of flu-like symptoms (see Signs and symptoms of acute HIV infection).19 It is important to note that the range and severity of symptoms vary, and some individuals may not consider themselves ill enough to seek care.19 During this period, HIV undergoes rapid viral replication. Clinicians who see individuals presenting with flu-like illness should ask them about their risk factors for HIV infection. Diagnostic evaluation for acute HIV infection includes HIV RNA viral load and HIV antibody testing.15,19,20 A significantly elevated HIV RNA and a negative or indeterminate HIV antibody test are considered diagnostic of acute HIV infection.19,20 Symptoms of acute HIV infection typically last 2 to 4 weeks, and this period generally consists of symptomatic care.20 Current guidelines recommend initiating ART at this time to preserve immune function and reduce infectiousness; however, clinicians should assess patient readiness, including adherence, prior to initiating therapy.15
Clinical evaluation
Initial clinical evaluation should include a complete medical and psychosocial history.20 For patients entering care, the history should include assessment of risk factors for HIV acquisition, signs or symptoms of acute HIV, and history of any opportunistic or AIDS-related infections. A detailed psychosocial assessment should include level of social support, who is aware of their HIV infection, risk of violence, level of personal safety, and assessment of financial and health resource needs.20
A detailed medication history should include inquiry about the use of over-the-counter and herbal medications. Several over-the-counter medications (such as proton pump inhibitors, H2 blockers, and certain herbal medications) can interact or are contraindicated with some antiretrovirals.15,20 For patients who have been on ART or who are currently prescribed ART, documentation of previous ART regimens and reasons for medication discontinuation (for example, drug resistance, intolerability, adverse events, or pill simplification and an assessment of current adherence to ART) should be obtained.20 A complete physical exam should assess for any evidence of possible opportunistic infections or common HIV-associated conditions, such as oral candidiasis, lymphadenopathy, evidence of cardiopulmonary compromise, hepatic disease, or any ano-genital infection or disease.20
Lab testing for the HIV-infected patient
Baseline lab evaluation includes assessment of immunologic and virologic status through measurement of CD4 lymphocyte count and HIV RNA viral load. HIV resistance testing should also be done at baseline to determine if an individual has any evidence of drug-resistant mutations.15,20 Presence of drug-resistant mutations reduces the efficacy of treatment and results in suboptimal therapy. Rates of transmitted drug resistance among antiretroviral-naive individuals have been estimated to be as high as 20% in some populations.21
There are currently two types of resistance tests available: genotypic and phenotypic assays. Genotypic testing identifies the presence of genetic mutations and predicts resistance based on the resistance pattern of viruses with similar mutations. Phenotypic testing is a more advanced form of resistance testing that measures the patient's viral response against ART in vitro. Genotypic testing is sufficient for baseline testing and for those who may experience initial drug failure.15 Phenotypic testing is typically reserved for persons who have an extensive ART treatment history.15
Additional testing that should be obtained at the time of initial presentation (or through historical documentation) includes determination of viral hepatitis infection.20 Approximately 30% of individuals with HIV are coinfected with chronic hepatitis C, and 5% to 10% have chronic hepatitis B infection.20 Individuals found to be susceptible to hepatitis A or B should be vaccinated.20 Testing should also be done for tuberculosis (TB). Persons found to have latent or active TB should be offered treatment.15,20
Other tests that are specific to HIV include HLA-B5701 and tropism testing. These tests are usually obtained prior to prescribing specific antiretrovirals. HLA-B5701 is a genetic test that is correlated with a hypersensitivity reaction to abacavir, a nucleoside analogue. Persons found to have presence of HLA-B5701 should not be prescribed abacavir-containing regimens and should have abacavir noted as an allergy.15 The tropism test is used prior to prescribing maraviroc, a CCR5 inhibitor.15 The tropism test can determine if a patient's virus will respond to this medication. Testing for HLA-B5701 and tropism can be done at baseline or prior to initiation of either of these medications.15
After the initial baseline lab studies are complete, persons should be monitored periodically to assess virologic and immunologic status (see Recommended baseline lab and diagnostic testing for HIV). Frequency of testing should be tailored to the individual. For persons who are newly initiated on ART, more frequent testing should occur to assess for virologic response and early toxicity.15,20 For the majority of patients, lab monitoring occurs every 3 to 4 months.20 For patients who have been stable on ART and have viral loads below the level of detection, monitoring can be extended to every 6 months.15 In addition to monitoring CD4 and HIV RNA viral load, ongoing monitoring of lipids, renal function, serum glucose, and hepatic function should be performed regularly.15
Opportunistic infection prophylaxis and treatment
For patients who are noted to have advanced HIV infection with CD4 counts less than 200 cells/mcl, appropriate opportunistic infection prophylaxis should be initiated.22 Prophylaxis against PCP, toxoplasmosis, and Mycobacterium avium complex should be started in persons who meet specific CD4 cell thresholds (see Common medications used for opportunistic prophylaxis).
Individuals with evidence of active opportunistic infections should be treated according to disease-specific recommendations.22 ART initiation is beneficial in these instances, especially in conditions for which effective treatments are limited, such as progressive multifocal leukoencephalopathy or cryptosporidium.15 For persons with evidence of active TB, treatment of active TB should be started as soon as possible, and ART may be postponed by a few weeks to minimize adverse reactions from overlapping toxicities.15
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS) is a syndrome in which persons with severe immune suppression (for example, CD4 count less than 200 cells/mcl) may be at risk for after initiation of ART.23 Individuals who have a rapid increase in CD4 levels after initiation of ART may experience a paradoxical reaction typically characterized by fever, malaise, and potential unmasking of an underlying opportunistic infection.23 Persons who experience signs or symptoms of IRIS shortly after treatment initiation can be managed with supportive therapy and treatment of any underlying infection.20,22,23 Use of corticosteroids and inpatient admission may be warranted in more severe cases.23 Most individuals are able to remain on ART during this period.23
Treatment considerations
In the United States, the Department of Health and Human Services (DHHS) and the International Antiviral Society-USA (IAS-USA) both issue treatment guidelines for the HIV treatment.15,24 These guidelines are regularly updated based on the latest evidence.
Both sets of treatment guidelines recommend treatment for everyone with HIV; however, the strength of the recommendations varies based on the patient's CD4 count (see Treatment guidelines for HIV-1 infection in adults and adolescents in the United States).15,24 Although the level of evidence for treatment in persons with less than 500 cells/mcl is less robust, experts feel that the treatment of all patients is one of the only ways to end the epidemic.15,24 Recent data have demonstrated that the risk of transmission of HIV is significantly reduced if the source patient has an undetectable viral load.25
For women who are pregnant at the time of diagnosis, initiation of ART is warranted, as evidence has shown that effective treatment of mothers during pregnancy can significantly reduce the risk of vertical transmission.15,26 Pregnant HIV-infected women should be referred to a specialist who is familiar with monitoring and managing pregnancy in the setting of HIV infection.26
Choice of antiretrovirals
All recommended treatment options consist of a combination of medications that target different parts of HIV's replication cycle. All preferred regimens consist of a combination of two nucleoside analogues paired with a nonnucleoside analogue, a protease inhibitor, or an integrase strand inhibitor. Both IAS-USA and the DHHS offer suggestions for initial regimens in antiretroviral-naive individuals (see U.S. DHHS and IAS-USA treatment options for ART-naive individuals).15,24 The choice of treatment should be based on several factors, the primary one being baseline drug resistance.15 If there is evidence of drug resistance on genotypic testing, then drug choices should be tailored in order to provide the patient with the best treatment choice possible. If there is no drug resistance to current regimens, then secondary issues should be considered, such as baseline HIV RNA viral load, use of medications that may alter drug metabolism, comorbidities, adverse reaction profile, and patient preference regarding pill burden, dosing requirements, and adverse reactions. Both guidelines emphasize that patients should be assessed for readiness and ability to adhere to medications prior to starting.15,24 Inconsistent adherence and nonadherence can lead to drug resistance and limit future treatment options.
Complications of chronic infection
As individuals are living longer, the diseases and comorbidities not previously seen in the HIV epidemic are emerging. The most common complications that are seen in the aging HIV population include metabolic complications, such as diabetes, cardiovascular disease, renal disease, liver disease, and an increase in non-AIDS-defining malignancies, such as anal cancer.3,5,15,20,27
Metabolic complications of long-term antiretroviral use include alterations in lipid synthesis, resulting in hyperlipidemia and impaired glucose synthesis, which can lead to diabetes; both of these can contribute to greater risk for cardiovascular disease in the HIV population.5 Patients should be monitored closely for alterations in lipid and glucose metabolism, and traditional treatments (including therapeutic lifestyle modification-especially tobacco cessation) should be implemented with patients.20
Renal and bone complications are a growing concern for many patients with HIV, especially those on tenofovir-containing regimens. Tenofovir is a nucleotide reverse transcriptase inhibitor that is contained in several of the preferred first-line drug combinations. Although it is a highly effective agent in the treatment of HIV, it unfortunately has the risk of impaired renal function and altered bone metabolism.28,29 Patients who are on ART should be monitored closely for alterations in renal function.20 Osteoporosis and osteopenia have also been seen in growing numbers of HIV patients on long-term therapy and in those who are aging.29 Screening for osteopenia should be considered in patients age 50 years or older and in those who have been on tenofovir-containing regimens for many years.20
Hepatic disease, especially chronic hepatitis C virus (HCV) infection and end-stage-liver disease, has become one of the leading causes of morbidity in the HIV population.5,30 Liver-related deaths now account for a greater number of deaths in persons with HIV compared to opportunistic infections.30 Patients with chronic hepatitis B virus (HBV) or chronic HCV infection should be screened and assessed for treatment.15 Older HCV treatment regimens (peg-interferon and ribavirin) had poor response in HIV/HCV coinfected patients compared to HCV mono-infected patients. Newer HCV direct-acting antivirals have shown favorable outcomes in persons with HIV/HCV coinfection.31 In patients with HIV/HCV coinfection, referral to a specialist who has experience in managing and treating HCV or to a clinical trial should be considered, as the management of treating HCV in the coinfected patient can be complex.
The rates of non-AIDS-defining malignancies have also been on the rise.27 The incidence of certain cancers, such as anal cancer associated with human papilloma virus (HPV) infection, has been noted to be significantly greater in persons with HIV compared to the non-HIV infected population.27 Although the exact mechanisms remain unclear, it is thought that persons with HIV are less able to clear HPV infection and are more likely to be infected with other high-risk oncogenic strains of HPV compared to the non-HIV-infected population.32 Based on this increased prevalence of anal cancer, some experts recommend annual anal-rectal digital exams to identify masses or signs of anal cancer.20,26 The use of routine anal cytology ("anal Pap") to screen for anal cancer remains controversial and has limited evidence. The current practice guidelines have given anal cytology a grade CIII rating, meaning that this intervention is optional and is based primarily on expert opinion.22
Patient education and retention in care
Patient education should begin with an assessment of the individuals' knowledge of HIV-including transmission, treatment, and prevention.20 As noted previously, patients with HIV are living longer, but one of the keys to increased life expectancy is based on the fact that patients receive appropriate care and treatment. The NP should emphasize the importance of not only medication adherence (to prevent drug resistance) but adherence and engagement with continuous primary care. Data have shown that of all persons tested for HIV, approximately 75% are connected with care, 30% receive ART, and 24% achieve an undetectable viral load.33 Therefore, it is critical for the NP to establish a trusting relationship with patients in order to remain in treatment and care. A patient's perceived relationship with their medical provider has been positively associated with retention and engagement in care.33
Other patient education that should be provided continually throughout treatment includes counseling on behaviors that reduce or minimize possible transmission of HIV to others and acquiring other infections or superinfections with possible drug-resistant strains of HIV.20 Given the chronic nature of HIV and the greater incidence of chronic disease, counseling and education related to the benefits of exercise, diet, and maintaining a healthy weight should be incorporated into primary care visits.20
Advances in prevention
There have been considerable advances in HIV prevention science over the past decade. There has also been a growing body of research in preexposure prophylaxis (PrEP) as a means of prevention. PrEP is a strategy where HIV uninfected individuals take ART on a daily basis to prevent infection. This differs from postexposure prophylaxis in that patients take medications before their exposure versus taking treatment following a high-risk incident. Tenofovir/emtricitabine is the drug that has been studied extensively as an option for PrEP and recently received approval from the FDA to expand labeling for use as HIV PrEP.34 The CDC has issued two sets of guidance for clinicians on the use of PrEP in both high-risk MSM and high-risk heterosexuals.35,36 The long-term safety and efficacy of tenofovir/emtricitabine as PrEP are still unknown. Individuals who are placed on PrEP should have their HIV status and renal function monitored and should be screened for other sexually transmitted infections at least every 3 months.35,36
Treatment for persons living with HIV, regardless of CD4 count, is now recommended. This is (in part) an effort to reduce an individual's level of infectiousness. Data from one landmark study, HPTN 052, demonstrated that heterosexual couples in sero-discordant relationships had a 96% reduction in the risk of infection if the partner with HIV was on treatment and had an undetectable HIV viral load.25 These data, along with the newer PrEP data, provide tangible opportunities to end the HIV epidemic.
Implications for advanced nursing practice
The field of HIV primary care has witnessed significant change over the past 30 years, and new advances in prevention and treatment continue to improve the lives of persons living with HIV and those at risk for HIV infection. The need for clinicians who are well versed in the management of chronic disease in the setting of HIV will continue to grow. The NP is in an ideal position to manage and treat HIV in both the primary and acute care settings.
Signs and symptoms of acute HIV infection15,19
* Fever
* Fatigue
* Pharyngitis
* Headache
* Mucocutaneous ulcerations
* Myalgia
* Thrombocytopenia
* Transaminitis
* Urticaria
* Rash
* Generalized lymphadenopathy
* Neurologic symptoms (for example, aseptic meningitis and cranial nerve palsies)
* Arthralgia
* Anorexia
Recommended baseline lab and diagnostic testing for HIV15
* CD4 count
* HIV RNA viral load
* HIV genotype
* Complete blood cell count
* Alanine aminotransferase, aspartate aminotransferase, Total Bilirubin
* Urinalysis
* Creatinine, blood urea nitrogen
* Fasting lipid profile
* Purified protein derivative or interferon gamma release assay
* Fasting glucose or HgA1C
* Hepatitis A, B, and C serologies
* Toxoplasma IgG
* Rapid plasma reagin
* Gonorrhea and chlamydia screening
* Pregnancy test
* HLA-B5701*
* Tropism testing**
*If considering use of an abacavir-containing regimen. Persons with presence of HLA-B5701 should not be given abacavir due to possibility of potentially fatal hypersensitivity reaction.
**If considering use of CCR5 inhibitor.
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