Michael S. Saag, M.
This journal article begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, where available. The article concludes with the author's clinical recommendations.
A 28-year-old woman is brought to the emergency department following a car collision. She has no clinically significant injuries other than a fractured bone. A urine drug screening is positive for opioids and marijuana. As part of a universal screening program, she is tested for human immunodeficiency virus (HIV) infection, and the results are positive. The patient is single and heterosexual, and reports that she does not use injectable drugs but occasionally trades sex for drugs. She has not been previously tested for HIV. Her other routine laboratory studies are normal except for mild lymphopenia. How would you further evaluate and treat this patient?
When acquired immunodeficiency syndrome (AIDS) was first identified in the early 1980s, it was believed to be restricted to a small number of at-risk groups. As more information became available about the epidemiological picture of HIV transmission, it became clear that the infection was transmitted primarily through sexual contact and blood (including injection drug use), as well as perinatally. In the United States, HIV type 1 (HIV-1) is the predominant virus, while HIV type 2 (HIV-2) is endemic in other areas of the world (e.g., West Africa).
In 2018, approximately 38,000 new cases of HIV infection were diagnosed in the United States and its territories. Although perinatal transmission in the United States has declined to very low levels due to routine HIV screening and the initiation of antiretroviral therapy (ART) for HIV, cases of women infected during pregnancy, adolescents, and adults decreased by only 7% between 2014 and 2018.4 Since the 1980s, the populations most affected by HIV infection have changed, and HIV infection is now disproportionately diagnosed in people who are poor, marginalized, and face significant barriers to healthcare. In 2018, 21% of new HIV infections were diagnosed in young people, 69% were diagnosed in men who have sex with men, 10% in people who inject drugs, 42% in Black people, and 27% in people of Hispanic or Latino descent. A quarter of all new cases occur in white people, who make up 73% of the population.
It is estimated that 1 in 7 people living with HIV in the United States are unaware of their infection. Many people at risk, particularly members of racial and ethnic minorities, do not have regular access to medical care and therefore do not receive a diagnosis until they have advanced disease, when treatments may be less effective and the risk of death is higher.
In 2019, the United States launched the "Ending the HIV Epidemic" plan with the goal of reducing the number of new infections by 75% by 2025 and by 90% by 2030. The plan includes four components: identifying all people with HIV infection, preferably early; successfully treating them with antiretroviral therapy (ART); preventing new infections; and responding rapidly to outbreaks as they occur. The foundation of the first two components includes minimizing gaps in diagnosis, improving linkage to care, rapidly initiating HIV therapy, and maintaining viral suppression through successful retention in care.
HIV TEST
US guidelines recommend that all sexually active people get tested for HIV at least once, and that those at ongoing high risk of infection get tested at least once a year. People at high risk are defined as those with an incident sexually transmitted infection; sexual partners of people with sexually transmitted infections; people who have had more than one sexual partner (or whose sexual partners have had more than one partner) since their most recent HIV test; people who inject drugs; and people who exchange sex for money or drugs. Testing is also recommended after a diagnosis of incident sexually transmitted infections and during pregnancy.
According to data from the Centers for Disease Control and Prevention (CDC) National HIV Surveillance System, more than 75% of people in high-risk categories who had seen a primary care provider in the previous year were not offered an HIV test.5 Many patients with undiagnosed HIV infection had multiple healthcare visits before receiving an HIV test. This lack of testing is a failure of the healthcare system because each encounter is an opportunity to reduce the incidence of HIV transmission. Up to 38% of new HIV infections are transmitted by people who are unaware of their HIV status. Furthermore, once HIV infection is identified and treated appropriately to maintain HIV RNA levels below 200 copies per milliliter, patients can lead nearly normal lives and do not transmit the virus to others.
Several studies have shown that in healthcare settings (including emergency departments and sexually transmitted infection and primary care clinics), more HIV infections are identified using routine opt-out testing (i.e., all adult patients are informed that HIV testing is available but they can choose not to participate) than with physician-directed testing. Recommendations for opt-out testing have been in place since 2006. Routine testing in the emergency department has been shown to be cost-effective.
Many tests are available to accurately diagnose HIV infection. Choosing the most appropriate test for a given clinical presentation depends on understanding the natural history of HIV infection (i.e., which markers are present at a given point after infection), the sample volume, and the test's performance specifications. During the window period, before the establishment of viremia on day 5, infection cannot be detected. Between days 6 and 8, the virus can be detected by a nucleic acid amplification test (NAAT). Viral proteins (p24 antigen) can be detected between days 13 and 20. Antibodies, initially in the form of IgM, are detectable by day 20, and IgG is detectable by day 30. Most patients present well after the initial infection, when both antibody and nucleic acid tests are positive.
Recommended laboratory tests for detecting HIV in serum or plasma samples. Due to the high cost of NAAT, combination antigen-antibody tests, which use the p24 antigen to identify patients in the early stages of infection, are now the standard tests in hospital and commercial laboratories. Most of these tests can detect both HIV-1 and HIV-2 infections.
Varias pruebas rápidas disponibles en el punto de atención utilizan una de dos técnicas: flujo lateral o flujo continuo. Una vez que los anticuerpos se unen a los antígenos, son detectados por un indicador. Las pruebas rápidas pueden utilizar sangre completa (<10 a 50 μl) recogida por punción digital o un hisopo oral como muestras; estas pruebas son convenientes y fáciles de administrar. Aunque la sensibilidad y la especificidad de estas pruebas suelen ser superiores al 98%, las pruebas de laboratorio son más precisas, especialmente en la infección temprana, y son necesarias para confirmar cualquier diagnóstico realizado sobre la base de una prueba rápida en el lugar de atención.
All individuals diagnosed with HIV infection should be referred for initiation of antiretroviral therapy (ART) and long-term follow-up. According to 2018 CDC surveillance data, only 78% of patients are linked to care within 30 days of diagnosis, and sustained viral suppression is achieved in only 55% to 60% of people (and an even lower percentage of infected adolescents and young adults) diagnosed with HIV.
The sooner an initial clinical visit is scheduled after diagnosis, the more likely the patient is to attend.23 A trial in sub-Saharan Africa showed that “immediate” initiation of ART at the time of a positive home test result increased adherence to treatment. Similar findings related to immediate initiation of therapy at the testing site have been reported in resource-rich countries, although structural barriers often block the implementation of immediate therapy, especially in busy emergency departments. In the United States, “rapid” initiation of ART, within one week of diagnosis, is the recommended practice. Establishing an active rapport with the patient, providing assistance in scheduling the first appointment, maintaining contact with the patient until the first visit, and addressing any barriers to attending the first appointment (e.g., transportation) are associated with a higher incidence of adherence to treatment.
A comprehensive intake assessment should be performed at the initial visit. The medical history should focus on the risk to others associated with the patient's exposure, as well as the patient's sexual health, ongoing substance use (including alcohol), and mental health disorders. A physical examination should be performed to assess for signs of advanced HIV infection, such as thrush, vaginal candidiasis, herpes simplex virus infection, Kaposi's sarcoma, lymphadenopathy, retinopathy, altered mental status, and wasting. Counseling should address the implications of an HIV diagnosis, the importance of disclosing the patient's HIV status to some trusted friends or relatives (for emotional support) and established sexual partners, and potential barriers to attending future appointments (e.g., lack of transportation, food insecurity and homelessness [which may cause a person to prioritize daily survival over medical visits], and interpersonal violence). Specific topics of discussion regarding preventing transmission to others should include routine use of condoms during sexual activity and avoiding sharing needles or other equipment during intravenous drug use.
Patients should be assured that they can expect a near-normal life expectancy and no risk of transmission to others once viral suppression is achieved and maintained with ART. From 2011 to 2017, among patients receiving standard ART regimens, the incidence of death 5 years after diagnosis differed by only 2.7 percentage points from that of age-matched controls.
With rare exceptions, ART should be started at the first clinic visit. The main reason for not starting treatment is that the patient identifies as an "elite controller" (i.e., someone with no detectable HIV RNA at presentation) or is not ready to start treatment for personal reasons. Retention to care improves when ART is prescribed at the initial visit and not delayed.
Guidelines suggest using integrase chain transfer inhibitor (ICSI)-based therapy with tenofovir (either tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide fumarate [TAF]) and lamivudine (3TC) or emtricitabine (FTC). Often, ART is prescribed before initial laboratory results are available; therefore, at the first visit, initial therapy should be limited to bictegravir-FTC-TAF or dolutegravir plus a fixed-dose combination (TDF-FTC, TDF-3TC, or TAF-FTC) due to its effectiveness, acceptable side effect profile, activity against hepatitis B virus (HBV), and a higher barrier to resistance development than other options. Treatment regimens can be adjusted once HIV RNA levels, CD4 count, and renal, hepatic, HBV, hepatitis C virus (HCV), and HIV data are available. These data may indicate that treatment can be simplified to a single two-drug tablet (dolutegravir-3TC). Recommended ART regimens have achieved sustained virologic suppression in over 90% of patients in clinical trials.
Primary prophylaxis against opportunistic infections in people with HIV infection.
Initiating ART in patients with active opportunistic infections or underlying conditions, and in pregnant women, is outside the scope of this review. In general, using a regimen that includes an INSTI (inhibitory-derived corticosteroid) that does not require booster therapy with cobicistat is often the best option in patients with these conditions due to the potency, pharmacokinetic profiles, and reduced drug interactions associated with these regimens.
Follow-up visits should begin 4 to 6 weeks after starting ART and then every 3 to 4 months until virological suppression is achieved. Once suppression is maintained for one year, follow-up visits should be every 6 months. At each visit, assessment of adherence to the ART regimen and any adverse effects is essential. Any difficulties with the regimen should be addressed during the visit, and the regimen should be changed if warranted. Testing for sexually transmitted infections, ongoing substance use (including alcohol), mental health disorders, and barriers to maintaining health (including housing problems, food insecurity, domestic violence, and other social determinants of care) should be performed, and the patient should be assessed for sexually transmitted infections, ongoing substance use (including alcohol), mental health disorders, and barriers to maintaining health (including housing problems, food insecurity, domestic violence, and other social determinants of care). Changes in medication or adjustments in dosage may be warranted if new renal, hepatic, or hematological abnormalities are detected in laboratory tests. Counseling, ideally at the same care facility, should be available if the patient has a new or recurrent mental health disorder.
Not all patients achieve undetectable viral loads; some maintain a consistently high viral load between 50 and 100 copies per milliliter due to a large reservoir of latently infected cells. In such patients, replication ceases with ART, and no further treatment adjustments are necessary. Conversely, if a viral load is measured above 50 copies per milliliter after prior viral suppression to 50 copies per milliliter or less, the measurement should be promptly repeated, and medication adherence and the side effect profile should be assessed. A confirmed HIV RNA level above 200 copies per milliliter should prompt viral resistance testing, including INSTI resistance testing if the patient is receiving an INSTI-based ART regimen.
More than 85% of patients receiving consistent care have maintained viral suppression indefinitely. After one year of stable viral suppression, clinical care typically transitions to primary care, and HIV becomes a secondary focus during routine visits. Patients may receive care from both an HIV clinic and a primary care provider, or primary care may be provided at the HIV clinic. Weight gain is common, especially among patients starting an INSTI-based regimen combined with TAF, although the mechanism of weight gain is not yet fully understood. Patients should be monitored for coexisting conditions, including obesity, diabetes mellitus and other metabolic disorders, cancer, and cardiovascular, renal, and hepatic diseases. These disorders occur more frequently and at a younger age in patients with successfully treated HIV infection than in age-matched controls.
More than 42% of new HIV infections are transmitted by people known to be HIV-positive but who are no longer receiving care; this underscores the need for effective retention-in-care strategies. Best practices to achieve this goal are still being developed. Centralized care, the use of bilingual and bicultural teams, in-clinic buprenorphine treatment for patients with concomitant opioid use disorder, specialized jail-to-clinic transition services, behavioral interventions, and increased patient contact through navigation programs have been successful. Calling patients if they miss scheduled appointments is one of the most effective means of retaining patients in care. An intervention involving brochures, posters, and short verbal messages conveying the importance of ongoing health care visits was associated with a higher incidence of return for subsequent appointments than no such intervention.
With the success of antiretroviral therapy (ART) over the past two and a half decades, the population of people living with HIV is aging. In the United States, more than 50% of patients receiving care for HIV infection are over 50 years of age; 18% are over 60, and older people with HIV infection are at greater risk of poor health outcomes than similar-aged people without HIV infection. Cardiovascular, renal, neurocognitive, and mental health disorders occur at younger ages in people with HIV infection than in age-matched controls. Older patients with HIV infection tend to have worse outcomes than younger patients due to a greater likelihood of polypharmacy, frailty, social isolation, and stigma. More data are needed to guide care for patients as they age.
Professional guidelines are available regarding screening, selection of an ART regimen for individual patients, and primary care for patients with HIV infection. The recommendations presented here are consistent with these guidelines.
The patient described in the vignette was at risk of HIV infection due to opioid use disorder and her involvement in sex for drugs. The diagnosis, made through systematic exclusion screening in the emergency department, underscores the benefit of this approach, as otherwise, the diagnosis would likely have been made much later. An appointment at an HIV clinic should be scheduled within one week of diagnosis for a baseline assessment (a detailed social history and laboratory tests, including testing for other sexually transmitted infections and evaluation of CD4 count and viral load) and immediate initiation of ART. She should also be referred for substance abuse management. She should be counseled on disclosing her HIV status to trusted individuals and sexual partners, the importance of using condoms and avoiding needle sharing to reduce transmission, the need to continue ART as prescribed and return for follow-up, and the expectation of a near-normal life expectancy if viral suppression is achieved and maintained. At subsequent appointments, adherence and any adverse effects of ART should be routinely assessed, as well as substance use and other social factors that may interfere with adherence to ongoing treatment.