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I have a healthy patient without HIV risk factors who asks about HIV screening. How do I diagnose or exclude HIV infection🚧 施工中
I have a healthy patient without HIV risk factors who asks about HIV screening. How do I diagnose or exclude HIV infection?
Jean Luc Benoit, MD
CHIEF COMPLAINT
PATIENT
Mr. A asks his new primary care clinician whether he should get an HIV test. He states that he has “absolutely no risk factors for HIV,” and is a very healthy 21-year-old black man in a monogamous relationship with his girlfriend for 2 years. The girlfriend was tested for HIV 6 months ago when a Board of Health nurse notified her that she might have been exposed to HIV, and retested 3 months ago. Both HIV tests were negative, effectively ruling out HIV infection.
Mr. A first became sexually active at age 15. Over the last 6 years, he has had 4 female partners, with a bit of overlap between the relationships (he had 2 simultaneous partners for about 1 year). He has never had sex with a male. He uses condoms “pretty consistently.” He had Chlamydia trachomatis urethritis 3 years ago, but no other sexually transmitted infections. He has never used injecting drugs, although he smokes marijuana once or twice a week. He stopped drinking excessively when he met his current girlfriend. He does not recall an episode of mononucleosis-like illness with fever and lymph node enlargement. His past medical history, review of systems, and physical exam are otherwise unremarkable.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Undetected HIV infection
Textbook Presentation
Chronic HIV infection may present in a myriad of ways. Many patients are entirely asymptomatic in spite of long-standing HIV infection and advanced immune deficiency as demonstrated by an absolute CD4 T lymphocyte (CD4TL) count below 200 cells/mcL (immunologic AIDS). Some patients may have symptoms that are often seen with HIV but are nonspecific, such as chronic diarrhea, seborrheic dermatitis, multiple molluscum contagiosum, poorly responsive psoriasis, and prurigo nodularis. Other patients have conditions that are strongly associated with HIV infection but are also encountered in non–HIV-infected persons, such as tuberculosis (TB), idiopathic thrombocytopenic purpura, nephropathy, nonischemic cardiomyopathy, herpes zoster (shingles), and non-Hodgkin lymphoma. Unfortunately, patients may be found to have HIV only when they are admitted to the hospital with a life-threatening AIDS-defining condition, such as Pneumocystis jirovecii pneumonia (PJP), Cryptococcus neoformans meningitis, central nervous system (CNS) toxoplasmosis, or primary CNS lymphoma (PCL).
Disease Highlights
A. Epidemiology of HIV in the United States
1. Prevalence: At the end of 2016, the Centers for Disease Control and Prevention (CDC) estimated that 1,130,000 persons were living with HIV infection in the United States of whom 973,846 persons had been diagnosed (an 11% increase over 2011).
2. Incidence: In 2016, there were 39,782 new HIV diagnoses, a 5% decrease from 2011.
3. The prevalence of HIV continues to increase in spite of the decreasing incidence because HIV-infected people live longer than in the past.
4. The sex ratio of new HIV infections is about 4 males to 1 female.
5. Men who have sex with men (MSMs) are disproportionately infected: male-to-male sexual contact accounts for 67% of new infections, heterosexual contact 24%, and injection drug use (IDU) 6%. About 3% of new infections are associated with both male-to-male sexual contact and IDU.
6. Racial and ethnic disparities are significant: blacks account for 44% of new infections; whites, 26%; Hispanics, 25%; and Asians, 2%.
7. Regional differences are also significant: the rates of new HIV diagnoses per 100,000 population are 16.8 in the South, 11.2 in the Northeast, 10.2 in the West, and 7.5 in the Midwest.
8. Transmission
a. Common modes of transmission include male-to-male sexual transmission, heterosexual transmission, and drug paraphernalia sharing among IDUs. Mother-to-child transmission during pregnancy, perinatally, or through breastfeeding has become uncommon in the United States (but remains common in Africa).
b. The higher the viral load, the greater the risk of transmission.
(1) The viral load is high in both acute HIV infection and advanced AIDS.
(2) Coinfections, such as TB or syphilis, increase the viral load.
(3) Effective antiretroviral therapy (ART) results in a very low viral load, decreasing the risk of transmission by at least 95%.
c. Sexual practices and sexually transmitted infections
(1) The highest risk of sexual transmission is among men with unprotected receptive anal intercourse and individuals with multiple sexual partners.
(2) The presence of genital inflammation or breakdown of genital mucosa increases the risk of transmission. Receptive anal intercourse is frequently associated with trauma as well as an increased risk of sexually transmitted infections.
(3) Sexually transmitted infections, whether they cause genital ulceration or not, significantly increase the risk of either transmitting or acquiring HIV.
(4) The risk is greater for persons with simultaneous rather than consecutive partners.
(5) During heterosexual intercourse, man-to-woman transmission is significantly more likely than woman-to-man transmission.
(6) Circumcised males are 65% less likely to acquire HIV through heterosexual intercourse, but circumcision does not reduce male-to-male sexual transmission.
(7) The consistent use of barrier methods (either male or female condoms) is about 95% effective in preventing HIV sexual transmission, but adherence is poor in most high-risk situations.
d. Transmission through blood transfusion has been nearly eliminated by blood product screening. The risk associated with blood transfusion in the United States is estimated at < 1 in 1,800,000 units.
e. Mother-to-child-transmission is common without ART prophylaxis. Effective therapy markedly reduces this risk (see below).
B. HIV and its target, the CD4TL
1. The main target cell of HIV is the CD4TL. The HIV surface protein GP 120 binds first to the main HIV receptor, the CD4 receptor. Second, the surface protein binds to an HIV chemokine co-receptor, either CCR5 or CXCR4. HIV also infects secondary target cells that carry these receptors, such as macrophages, dendritic cells, and stem cells.
2. HIV replicates mostly in activated CD4TL: 99% of HIV detected in the blood comes from recently infected, activated CD4TL.
3. In acute HIV infection, there is a very rapid decrease in the number of CD4TL in the gut-associated lymphoid tissues but only a moderate and partially reversible decrease in the blood CD4TL.
4. In chronic HIV infection, the absolute CD4TL count decreases slowly in the blood. About 2 billion CD4TL are destroyed and replaced every day. Both HIV-infected and noninfected CD4TL (innocent bystanders) are destroyed.
5. In most infected individuals, the high rate of CD4TL death results in a progressive fall in the blood CD4TL.
6. When the absolute CD4TL count falls below 200 cells/mcL, immunologic AIDS is diagnosed.
a. The patient is susceptible to virulent pathogens, opportunistic infections (OIs), and AIDS-defining malignancies. The lower the CD4TL count, the greater the risk of any OI and the greater the spectrum of OIs seen.
b. Some patients acquire an OI (such as TB) or AIDS-defining malignancy (such as lymphoma) at a CD4TL higher than 200 cells/mcL; in these cases clinical AIDS is diagnosed.
7. About 5% of patients have stable CD4TL over many years (“long-term nonprogressors”). Rarely, the viral load is also undetectable (“elite controllers”).
8. Accelerated evolution of HIV and quasi-species
a. HIV evolves rapidly due to both a high rate of mutations introduced by an error-prone reverse transcriptase and a very high replication rate (10 billion new HIV virions per day). This allows for the rapid development of genetic variants (quasi-species), which may escape immune responses and become resistant to a number of antiretroviral agents.
b. Effective ART requires complete suppression of viral replication to prevent new cell infections and the production of mutations associated with drug resistance.
C. Staging
1. Stages of HIV infection include viral transmission, primary infection, seroconversion, clinically latent period, early symptomatic HIV infection, and AIDS.
a. Primary HIV infection
(1) Most patients with primary HIV infection are symptomatic: many have nonspecific symptoms like fever, diarrhea, arthralgia, headache, or flu-like symptoms. Some present with a striking mononucleosis syndrome that includes fever, sore throat, rash, oral aphthous ulcers, and lymphadenopathy. Occasionally, they have neurologic complications, such as aseptic meningitis, acute encephalopathy, or Guillain-Barré syndrome.
Acute HIV infection should be considered in patients with mononucleosis syndromes when tests are negative for Epstein-Barr virus (negative EBV viral capsid IgM) and cytomegalovirus (negative CMV IgM). Diagnosis of acute HIV requires a high index of suspicion.
(2) In primary HIV infection, the HIV viral load is almost always > 10,000/mcL and usually > 100,000/mcL. Therefore, a low-positive viral load in this context should be repeated to rule out a false-positive test.
b. Seroconversion
(1) Seroconversion rapidly causes a fall in HIV viral load (due to both humoral and cellular immune responses).
(2) After about 6 months, the viral load is set at a level that remains relatively stable in any specific patient (the viral load “set point”) but varies from patient to patient.
(3) In the absence of ART, the set point predicts the rate of disease progression (higher viral loads are associated with more rapid declines in CD4TL counts).
c. Clinically latent period
(1) Following primary infection, viral replication continues primarily within activated CD4TL, with progressive destruction of the CD4TL pool.
(2) Persistent generalized lymphadenopathy is often seen.
(3) Progression to an AIDS-defining illness is more common in patients with higher viral loads and lower CD4TL counts.
(4) Progressive depletion of CD4TL renders patients increasingly susceptible to OIs and malignancies: AIDS is predominantly a T-cell immunodeficiency. However, multiple other immune responses are abnormal: for example, HIV-infected patients often have polyclonal hypergammaglobulinemia and fail to mount antibody responses to either Streptococcus pneumoniae infection or the administration of the 23-valent pneumococcal polysaccharide vaccine.
d. Early symptomatic HIV infection: At relatively high CD4TL counts (200–350 cells/mcL) HIV infection is associated with an increased risk of infections by virulent pathogens, especially pneumococcal pneumonia and TB.
e. AIDS
(1) Advanced HIV disease is accompanied by severe CD4TL depletion (below 200 cells/mcL) and infection with less virulent, opportunistic pathogens.
(2) Specific opportunistic pathogens are mostly encountered when the CD4TL count falls below a critical level.
(a) CD4TL count < 200 cells/mcL: PJP, oral candidiasis
(b) CD4TL count < 100 cells/mcL: Toxoplasma gondii brain abscesses, Candida esophagitis, C neoformans meningitis, disseminated histoplasmosis, and meningeal coccidioidomycosis
(c) CD4TL count < 50 cells/mcL: Cytomegalovirus (CMV) retinitis and Mycobacterium avium/intracellulare (MAI); the latter is also called disseminated M avium complex (MAC)
(3) AIDS diagnostic criteria
(a) CD4TL count < 200 cells/mcL (immunologic AIDS)
(b) AIDS indicator conditions (clinical AIDS):
(i) AIDS-defining malignancies: PCL, non-Hodgkin lymphoma, Kaposi sarcoma, and invasive cervical cancer
(ii) OIs: PJP, TB, disseminated MAC, recurrent bacterial pneumonia, esophageal candidiasis, cryptococcosis, progressive multifocal leukoencephalopathy (PML), toxoplasmosis, and cryptosporidiosis
(iii) Other AIDS indicator conditions: HIV-associated dementia and AIDS wasting syndrome (“slim disease”)
(c) Advanced HIV infection is defined as CD4TL count < 50 cells/mcL.
Evidence-Based Diagnosis
Similar to any other diagnosis, the positive predictive value is determined by 3 features: the pretest probability of disease, the sensitivity of the test, and the specificity of the test. Each feature must be carefully evaluated to interpret HIV results properly.
A. Estimating pretest probability of HIV infection
1. Risk factors include MSM, IDU, and multiple sexual partners.
2. The prevalence of HIV varies from 0.3% in the general US population to > 50% in very high-risk groups.
B. Diagnosis of HIV: the 3-step HIV screening sequence
1. The diagnosis of HIV infection utilizes antibodies to HIV and tests for HIV RNA and HIV p24 antigen.
a. HIV RNA and p24 antigen are present prior to HIV antibodies and allow for the diagnosis of early HIV infection prior to the presence of HIV antibodies (Figure 5-1).
Figure 5-1. Sequence of appearance of laboratory markers for HIV-1 infection. Approximately 10 days after infection, HIV-1 RNA becomes detectable by nucleic acid tests (NAT) in plasma and quantities increase to very high levels. Next, HIV-1 p24 antigen is expressed and quantities rise to levels that can be detected by fourth-generation immunoassays within 4–10 days after the initial detection of HIV-1 RNA. IgG become reactive 18–38 days or more after the initial detection of viral RNA. (Reproduced with permission from Centers for Disease Control and Prevention. Quick Reference Guide-Laboratory testing for the diagnosis of HIV infection: updated recommendations)
b. The CDC has recently recommended a 3-step HIV screening sequence to improve the sensitivity of early HIV diagnosis without increasing the rate of false-positive diagnosis (Figure 5-2).
Figure 5-2. Recommended laboratory HIV testing algorithm. (Reproduced with permission from Centers for Disease Control and Prevention. Quick Reference Guide-Laboratory testing for the diagnosis of HIV infection: updated recommendations)
(1) The first step is the fourth-generation HIV-1/2 antigen/antibody combination immunoassay: it detects both HIV 1/2 antibody (Ab) and HIV-1 p 24 antigen (Ag). Adding the p24 Ag to this test allows for recognition of early HIV infection before Ab is detectable.
(2) When the first step is positive, the second step of the sequence is the HIV-1/HIV-2 Ab differentiation immunoassay. This confirmatory test detects and differentiates Ab to HIV-1 and to HIV-2. The result is reported as HIV-1 Ab detected, HIV-2 Ab detected, non-differentiated HIV Ab detected, or no Ab detected.
(3) When the result of the second step does not confirm HIV (HIV-1 Ab is negative or indeterminate and HIV-2 Ab is negative), a third step is required, which is an HIV-1 nucleic acid test, usually the HIV-1 quantitative RNA viral load. A positive HIV-1 RNA viral load confirms HIV-1 infection. A negative HIV-1 RNA viral load rules out HIV infection.
(4) In summary, HIV-1 infection is only confirmed when 2 steps of the HIV screening sequence are positive.
2. Specificity and sensitivity of the 3-step HIV sequence
a. When both the first and either the second or the third tests are positive, the sensitivity > 99% and the specificity of the 2-step test is about 99.6%.
b. Very recent HIV infection prior to the appearance of p24 Ag will be negative on the HIV screening sequence. Because p24 Ag appears around 14 days after infection, only few primary cases of HIV are missed. Still, these patients may have poor outcomes and cause further HIV infections.
Prevention and Treatment
A. Prevention
1. As noted above, male and female condoms are about 95% effective in preventing HIV sexual transmission, but adherence is poor in many high-risk situations.
2. Blood product screening has virtually eliminated transfusion-associated HIV transmission in the United States.
3. Effective ART results in a very low viral load, decreasing the risk of transmission by about 95%. The “treatment as prevention” strategy aims to identify HIV infection early and start effective therapy, reducing the spread of HIV.
4. Preexposure prophylaxis (PreP)
a. A highly effective strategy of treating a seronegative person with a daily combination tablet that includes 2 antiretroviral drugs, tenofovir disoproxyl fumarate and emtricitabine to prevent HIV infection.
b. Should be offered to HIV sero-discordant couples and individuals at high risk for HIV infection.
c. To improve implementation, preexposure prophylaxis should be initiated and monitored by all primary care providers and not restricted to infectious disease and HIV specialists.
d. The cost of the preexposure prophylaxis combination is well covered by healthcare plans.
5. Needle-exchange programs are effective in preventing the spread of HIV in IDUs.
6. Mother-to-child-transmission
a. Most cases occur at term (intrapartum) and with breastfeeding, but there is a significant risk during pregnancy.
b. HIV-infected pregnant women are treated as soon as possible with ART so the viral load is undetectable during pregnancy and at the time of delivery.
c. Postpartum, mothers are told not to breastfeed and the neonates receive postexposure ART prophylaxis.
d. Women who do not reach a low viral load at term (viral load < 1000 copies/mL) are offered an elective cesarean section to decrease the risk of mother-to-child-transmission.
e. Intravenous zidovudine is given during labor if there is no documentation of an undetectable viral load.
f. This strategy has reduced mother-to-child-transmission by more than 90% in the United States.
B. Universal screening
1. More than 1 million people live with HIV in the United States, and 14% of them are unaware of their infection, which contributes to further spread of HIV.
2. In the absence of screening, many patients present with advanced immunodeficiency and OIs.
a. Such patients are often very ill and severely immunocompromised, and are at high risk for poor outcome.
b. Even if they do well on ART, most only partially recover their immune function.
3. Selective high-risk screening is inefficient
a. Although most HIV-infected patients have increased risk factors, clinicians do not consistently ask about risk factors and may not even consistently screen patients who present with another sexually transmitted or blood borne infection (“missed opportunities” for HIV testing).
b. Patients may not report risk factors accurately especially if they fear the clinician may be judgmental.
c. Not all HIV-infected patients have identifiable risk factors, especially if HIV prevalence is higher in the general population.
d. Therefore, selective HIV screening of high-risk individuals is very inefficient.
4. Universal HIV screening recommended
a. CDC recommends routine HIV screening for patients aged 13–64 years evaluated in all healthcare settings unless the prevalence of undiagnosed HIV infection had been documented to be below 0.1%.
b. The United States Preventive Services Task Force recommends universal voluntary HIV screening of adolescents and adults (2012).
c. Universal HIV screening has therefore become the recognized standard of care in the United States.
C. Treatment
1. The first encounter: the role of the primary care clinician
a. The first encounter is essential in establishing a good clinician/patient relationship.
b. Patients who have just found out they have HIV tend to be distraught and confused even if they are not totally surprised by the diagnosis.
c. Often patients do not believe that the diagnosis is correct (HIV denial).
d. Patients may believe wrongly that their life is over because they perceive that they will die soon from HIV, will be unable to live a productive and fulfilling life, will face severe drug adverse effects, or might infect their household contacts. Such misconceptions also enhance the stigma associated with HIV.
e. The primary care clinician should take the required time necessary to reassure the patient that HIV can be managed well on a simple ART regimen with acceptable side effects in most people, and clarify the diagnosis, transmission, and natural history.
f. Providing ample time to answer questions and deal with anxiety, depression, addiction, housing issues, healthcare insurance coverage, and partner notification is important.
g. Referral to an infectious disease specialist (or internist with specialized HIV practice) is required, but the primary care clinician should strongly consider continuing to provide primary care to his or her HIV-infected patients.
2. The role of the HIV specialist
a. The HIV specialist works with nurses, social workers, case managers, HIV support groups, AIDS legal support groups, addiction specialists, and psychiatrists to ensure effective HIV care and maximize adherence to ART.
b. HIV-infected patients who adhere to ART are highly likely to achieve an undetectable HIV viral load and do well over many years.
c. HIV-infected patients who do not take their ART as prescribed progress to AIDS and their virus may acquire resistance mutations to multiple agents.
3. Laboratory testing
a. Assessment of current immunocompetence: absolute CD4TL count and CD4/CD3 percentage
b. Test the HIV isolate: baseline HIV viral load and HIV genotype to look for transmitted resistance-associated mutations before any ART is introduced
c. Test for common coinfections
(1) Patients should be screened for syphilis, hepatitis B, hepatitis C, T gondii (IgG), C trachomatis and Neisseria gonorrhoeae infection (in women and MSM) and human papillomavirus–related carcinomas (cervical cancer in women and anal cancer in MSM).
(2) Latent TB infection
(a) The purified protein derivative (PPD) is the intradermal injection of tuberculin. In HIV and other immunocompromised patients, PPD is considered positive if there is > 5 mm of induration at 48–72 hours. The test has significant limitations:
(i) First, patients have to return for the reading 48–72 hours later.
(ii) Second, the test is not specific: false positive PPD frequently occurs due to prior exposure to nontuberculous mycobacteria or prior administration of Bacille Calmette-Guerin (BCG).
(iii) Third, PPD can be falsely negative when a patient infected with HIV is unable to mount a delayed-type hypersensitivity response, usually due to a low CD4 count.
(b) An interferon gamma release assay (IGRA) is frequently preferred to PPD in HIV patients.
(i) First, IGRA is much more specific for latent TB infection and is not affected by prior BCG vaccination, although it can be positive with prior exposure to Mycobacterium kansasii or Mycobacterium marinum.
(ii) Second, when the patient is unable to mount an immune response to the M tuberculosis Ag included, IGRA will be indeterminate rather than negative. An indeterminate IGRA test is inconclusive and does not increase the probability of TB or latent TB infection.
A positive PPD or IGRA never proves active TB, and a negative PPD or IGRA never rules out active TB.
d. Baseline labs: CBC, comprehensive metabolic panel, lipid panel; glucose-6-phosphate dehydrogenase (G6PD) level, in case dapsone or primaquine required for PJP
4. Immunizations
a. The response to vaccines often is suboptimal unless the CD4TL count is > 200 cells/mcL. The response to conjugated vaccines is better so the tetanus/diphtheria/acellular pertussis (TDAP) vaccine and the 13-valent conjugated pneumococcal vaccine (Prevnar 13) are likely to be effective even at lower CD4 count.
b. Since ART often leads to significant immune reconstitution, delaying or repeating immunizations may be useful.
c. The recommendations for vaccinations in HIV-infected persons is summarized in Table 5-1.
Table 5-1. Vaccinations in HIV-infected persons.
5. ART
a. ART has revolutionized HIV care. AIDS-defining illnesses, mortality, and hospitalizations have decreased 60–80% since the introduction of ART.
b. Effective ART requires complete suppression of viral replication to prevent the emergence of mutations associated with drug resistance.
c. The cornerstone of therapy is the simultaneous and uninterrupted use of generally 3 antiretroviral drugs to which the virus is susceptible. A fourth drug may be added to boost the level of one of the active drugs. Often, it is possible to select a combination tablet that includes all required drugs, allowing a 1 pill once a day regimen.
d. Complete suppression is realistic in most patients, prevents the worsening of immune deficiency and results in at least partial immune reconstitution.
e. Lifetime ART is necessary to prevent viral rebound due to non-replicating, latent HIV in the reservoirs (including macrophages, resting CD4TL, memory cells and stem cells).
f. Even in patients with a so-called “undetectable viral load,” there is a “residual HIV viremia” (1–5 copies/mL), which can only be assessed with advanced research techniques. When ART is interrupted, the residual viremia re-infects activated CD4TL, leading to a relapse. HIV is not curable with ART alone.
Lifelong ART is required for all HIV infected persons
g. Indications for ART
(1) ART is indicated all HIV-infected patients, including those with acute HIV infection and chronic symptomatic or asymptomatic infection
(2) With OIs that involve the brain, ART is delayed to prevent immune-reconstitution-inflammatory syndrome (IRIS) and cerebral edema associated complications.
(3) Treating an infected patient prevents transmission (epidemiologic benefit)
(a) Treating HIV-infected pregnant women prevents mother-to-child-transmission.
(b) Treating infected persons decreases transmission to sex partners.
h. Antiretroviral agents
(1) Antiretroviral drugs belong to 5 classes
(a) Nucleoside reverse transcriptase inhibitors block reverse transcription of viral RNA into DNA by incorporation in the elongating chain (chain terminators).
(b) Nonnucleoside reverse transcriptase inhibitors (NNRTIs) block reverse transcription of viral RNA into DNA by binding to the “NNRTI pocket” in the p66 subunit of reverse transcriptase.
(c) Integrase inhibitors prevent the integration of HIV DNA into the cellular DNA.
(d) Protease inhibitors inhibit the HIV protease, resulting in lack of cleavage of a viral polyprotein precursor.
(e) Entry inhibitors
(i) Ibalizumab, a recently approved anti-CD4 receptor monoclonal Ab binds to the D2 domain of the CD4 receptor, leading to conformational changes to the CD4 receptor and HIV surface protein complex, which prevents further steps required for viral entry.
(ii) Maraviroc prevents HIV cell entry by blocking the CCR5 chemokine receptor, a co-receptor for HIV surface protein. CCR5 receptor inhibitors are effective only if HIV is exclusively CCR5-tropic, and does not use CXCR4 at all. The use of the CXCR4 co-receptor increases in advanced HIV. The co-receptor tropism assay detects whether HIV is CCR5-tropic, CXCR4-tropic, or dual-tropic.
(iii) Enfuvirtide, an oligopeptide, blocks the fusion of the HIV envelope with the cell membrane (fusion inhibitor) by binding to the transmembrane glycoprotein gp41.
i. Adherence
(1) Patient adherence is key. The regimen should be easy to take and well tolerated. Most patients are able to take a single tablet once a day that combines 3 antiretroviral drugs with limited adverse effects.
(2) Adherence of 90–95% is required to maintain viral control and prevent resistance.
(3) High adherence has been shown to decrease morbidity and mortality.
(4) Moderately poor adherence (50–90%) still has still significant clinical benefits but promotes viral resistance, leading to eventual failure of therapy.
(5) Very poor adherence (below 50%) does not prevent progression to AIDS (nor select for resistance).
(6) Predictors of poor adherence include substance abuse, mental illness, lack of access to medical care or medications, lack of patient education, and poor trust between patient and clinician.
j. Testing for viral resistance
(1) Performed at baseline to detect transmitted resistance and whenever the patient fails to achieve or maintain an undetectable viral load on ART
(2) Both genotype and phenotype are available, but the genotype is preferred because it provides faster results, costs less, and is as clinically useful as the phenotype.
(3) Decisions are complex and require expert guidance. Databases of resistance-associated mutations help decision-making. Stanford University HIV-DB is a very useful tool that is free and readily available on the Internet.
k. Monitoring:
(1) Guidelines recommend monitoring viral load every 3 months and CD4TL count at intervals.
(2) Goal of therapy: undetectable viral load (< 20/mcL) by 4–6 months
(3) Failure to achieve viral suppression usually is secondary to patient nonadherence, HIV drug resistance, or both. Occasionally other factors are involved: malabsorption, drug interactions, selection of a suboptimal regimen with lower potency, and greater volume of distribution in late pregnancy.
6. Primary and secondary OI prophylaxis
a. Primary prophylaxis prevents the initial OI.
b. Secondary prophylaxis prevents subsequent symptomatic episodes after the initial OI (may not eradicate the infection but can prevent illness).
c. Primary OI prophylaxis
(1) The CD4TL cell count is the best predictor of susceptibility to OIs.
(2) ART raises CD4TL count in most but not all patients, and markedly decreases the risk of OIs.
(3) Susceptibility is determined by the current CD4TL count rather than the nadir CD4TL count.
(a) CD4TL < 200/mcL: PJP prophylaxis recommended
(b) CD4TL < 100/mcL: Toxoplasmosis prophylaxis recommended if Toxoplasma IgG is positive
(c) Isoniazid therapy for latent TB infection is recommended if PPD causes at least 5 mm of induration or the IGRA is positive.
d. Primary or secondary OI prophylaxis may be stopped in patients in whom ART restores the CD4TL count above the level recommended for primary prophylaxis.
7. Major socioeconomic barriers to diagnosis and treatment
a. Lack of timely access to high-quality healthcare
b. Only partial drug cost coverage
c. Poor support for treatment of drug addiction and psychiatric conditions
d. Entrenched homelessness
e. Poor care of some patients in jail
f. HIV-associated stigma remains an issue although significant progress has been achieved.
8. The HIV Care Continuum and HIV Elimination
a. One important goal of treatment as prevention is the prevention of new HIV infections. Patients on ART who achieve and maintain undetectable viral loads do not transmit HIV.
b. A second goal of treatment is to achieve the UNAIDS 90-90-90% targets: by 2020, 90% of the HIV-positive population diagnosed, 90% of diagnosed individuals on ART, and 90% of patients on ART virologically suppressed. Currently in the United States, of all persons infected with HIV, 86% are diagnosed, 63% are in care, 49% are retained in care, and 51% have a suppressed viral load (Figure 5-3).
Figure 5-3. The HIV Care Continuum. (Reproduced with permission from Centers for Disease Control and Prevention. Understanding the HIV Care Continuum.)
c. HIV elimination would require that the reproductive rate of HIV infection be kept below one new infection per 100 infected patients per year, which leads to a decrease of prevalence over time.
MAKING A DIAGNOSIS
As noted above, 3 factors determine the positive predictive value of the test: the pretest probability, the sensitivity, and the specificity. Mr. A is asymptomatic and denies high-risk behaviors. However, he may not truly be at a low risk of HIV, since he had a prior sexually transmitted infection and did not always use a condom with his 4 sex partners. His history of alcohol binges may also point to forgotten prior high-risk behaviors. The history of simultaneous sexual partners is also a risk factor. His pretest probability of HIV infection is therefore significantly higher than he believes.
A fourth-generation HIV-1/2 Ag/Ab combination immunoassay is positive. The HIV-1/HIV-2 Ab differentiation immunoassay confirmatory test detects HIV-1 Ab, confirming HIV-1 infection. Because of the excellent specificity of the combined tests, his posttest probability of HIV infection is > 99%. The CD4TL count is 150 cells/mcL (immunologic AIDS) and the HIV viral load is 80,000 copies/mcL (high). Toxoplasma IgG is negative. IGRA (quantiferon) is negative.
Have you crossed a diagnostic threshold for the leading hypothesis, HIV? Are other tests needed to exclude the alternative diagnoses?
CASE RESOLUTION
Mr. A is infected with HIV-1 and his CD4TL count is diagnostic of immunologic AIDS. At this point, primary prophylaxis with trimethoprim-sulfamethoxazole (TMP/SMX) is indicated to prevent PJP because the CD4TL count is < 200 cells/mcL. Prophylaxis for toxoplasmosis is not necessary since he is seronegative for T gondii. He does not need isoniazid since his IGRA is negative.
The patient should undergo blood testing for CBC with platelets, comprehensive metabolic panel, lipid panel, HBsAg, HBsAb, HBc total Ab, HCV Ab with reflex HCV viral load, G6PD level, and syphilis testing (using the reverse sequence syphilis algorithm). Urine nucleic acid test for Chlamydia and N gonorrhoeae is recommended. He should receive the influenza vaccine as well as two conjugate vaccines: TDAP and the conjugated 13-valent pneumococcal vaccine (Prenar-13), which are both highly immunogenic. Two months later he can receive the polysaccharide 23-valent pneumococcal vaccine (Pneumovax 23), but it is best to wait until the CD4 has increased > 200 cells/mcL to improve immunogenicity. Hepatitis B and hepatitis A combined vaccine series should also be offered after the CD4 has increased above 200 cells/mcL.
He is in a monogamous sexual relationship with an HIV seronegative, uninfected female partner. To decrease her risk of acquiring HIV, they should use barrier precautions (male or female condoms are 95% effective), and he should start ART to lower his HIV viral load to below the level of detection (treatment as prevention > 95% effective). If he is adherent to ART and his viral load is kept below 20 copies/mL, there is virtually no risk of transmission. However, the use of barrier precautions is a safety feature in case he developed a detectable viral load due to imperfect adherence to ART. Another approach if barrier precautions are not acceptable or adhered to is to provide preexposure prophylaxis with the combination of tenofovir disoproxyl fumarate and emtricitabine daily to his girlfriend. The tenofovir alafenamide and emtricitabine combination is not yet approved for preexposure prophylaxis but the DISCOVER trial is expected to provide this information by 2019. If effective, it would be associated with less nephrotoxicity and osteoporosis.