HIV DISEASE

HIV DISEASE

Current Diagnosis

• Revised national guidelines recommend universal screening for HIV infection for patients aged 13 to 64 years in all settings after notification that testing will be done, unless the patient specifically declines (opt-out testing). Patients with behavioral risk factors, sexually transmitted diseases, or tuberculosis should be screened annually.

• Acute HIV infection is recognized as a variable syndrome including fever, pharyngitis, rash, and arthralgias.

• As antiretroviral therapy has prolonged survival for patients living with HIV, non–HIV-related outcomes such as cardiovascular, liver, and renal disease have gained importance as preventable causes of morbidity and mortality.

Current Therapy

• Accumulating evidence suggests that earlier initiation of antiretroviral therapy improves clinical outcomes and reduces HIV transmission risk.

• Several classes and an increasing number of different fixed-dose combinations of antiretroviral medications give treatment-naive and treatment-experienced patients several therapeutic options.

• New guidelines for HIV treatment (including management of special situations such as HIV/TB co-infection) and pre-exposure prophylaxis for persons at high risk of incident HIV infection were released in 2012.

• At least one HIV-infected patient, who underwent a bone marrow transplant for leukemia, has been cured of HIV. Active research to identify the mechanisms underlying this cure is ongoing with the hope of identifying a strategy to cure all people living with HIV.

• The addition of Hepatitis C protease inhibitors has revolutionized treatment of Hepatitis C (HCV), a common co-infection, but caution is advised when treating HIV and HCV simultaneously because of drug-drug interactions.

• At least 16 patients have now been deemed “cured” of HIV. One underwent a bone marrow transplant for leukemia; the others, including a baby diagnosed at birth, achieved a functional cure after receiving combination drug therapy within weeks of acquiring HIV and are now able to maintain an undetectable viral load off of antiretrovirals.

Since its first description in the early 1980s, the acquired immunodeficiency syndrome (AIDS) has become one of the most devastating epidemics in human history. Millions of new infections occur every year, predominantly in resource-poor settings where access to diagnosis and treatment of human immunodeficiency virus (HIV) infection remains inadequate. The natural history of HIV infection remains one of progressive immune system dysfunction with inevitable acute and chronic infectious complications. With few exceptions, the inexorable decline in T-lymphocyte function eventually leads to the death of untreated patients. Remarkable advances in therapeutics, leading to the development of highly active antiretroviral therapy (HAART), have transformed HIV infection from an almost universally fatal illness to a chronic disease that can be managed over decades with an enlarging repertoire of treatment options. This chapter provides an overview of the current understanding of HIV pathogenesis and epidemiology and reviews guidelines for the initial evaluation and long-term management of HIV infection in adult patients.

Epidemiology

According to the Joint United Nations Programme on HIV/AIDS, an estimated 34 million people were living with HIV at the end of 2010; roughly half of them were women, and more than 2 million were children. Of the estimated 7400 new infections that occur daily, 96% occur in low- and middle-income countries, and approximately 1000 of those infected are children younger than 15 years of age. The prevalence of HIV infection in populations varies widely across the world, with the highest documented rates occurring in southern Africa, where prevalence rates derived from surveillance of asymptomatic pregnant women have exceeded 30% in some settings. AIDS is now the leading cause of death worldwide for persons aged 15 to 59 years, and this trend is associated with particularly dire social and economic consequences in sub-Saharan Africa, where more than half of global AIDS deaths occur. In some sub-Saharan countries such as Swaziland, Botswana, and Lesotho, life expectancy has been reduced by more than 20 years. However, with a rapid and significant increase in funding and commitment from the U.S. government (President’s Emergency Plan for AIDS Relief [PEPFAR]) and many multilateral agencies such as the Global Fund, a dramatic increase in prevention, care, and treatment services is now underway. A stabilization and initial trend illustrating a global decrease in AIDS deaths is being observed.

North America has experienced a striking decline in AIDS deaths since the advent of HAART, although a sizeable reduction in the annual number of new HIV infections has not yet been achieved. In the United States, an estimated 1.2 million people are living with HIV. The Centers for Disease Control and Prevention (CDC) estimates that 20% of these individuals are unaware of their HIV status. The CDC estimates that approximately 47,100 people were newly infected with HIV in 2010. Ethnic minorities, particularly African Americans, are disproportionately represented among those with new infections. As is the case worldwide, sexual contact accounts for the majority of HIV transmission for both men and women. In the United States, male-to- male sexual contact represents the mode of acquisition for the majority (61%) of new cases among men, whereas most women are infected via heterosexual contact. Injection drug use accounts for roughly 20% of new HIV infections in both men and women.

The risk of HIV transmission per exposure has been estimated from studies of discordant couples and cohort studies. The average risk of HIV transmission per coital act in serodiscordant heterosexual couples is approximately 0.1%. The presence of other sexually transmitted infections and higher viral load (VL) increase the risk of transmission; condom use and male circumcision considerably reduce the risk.

Female-to-male transmission is less effective than male-to-female transmission. Receptive anal intercourse is associated with a higher risk of transmission compared with vaginal intercourse. Even though the risk of transmission by oral sex is very low, it should not be considered completely safe.

Mother-to-child transmission can occur in utero, in the peripartum period, and during breast-feeding. The probability of transmission is most influenced by maternal plasma VL. Other risk factors include maternal CD4+ T-cell count (discussed later), hepatitis C infection, premature rupture of membranes, preterm birth, and duration of breast-feeding. In the United States, mother-to-child transmission has been markedly reduced (from 20%–25% to <1%) through routine HIV testing and effective interventions. These interventions include HAART, elective cesarean delivery if the VL is greater than 1000 copies per milliliter at week 38, and recommendation to avoid breast- feeding. The risk of HIV transmission with breast-feeding is 10% to 16% in the absence of intervention and is thought to be highest during the first 2 to 4 months. Factors that increase transmission include inflammatory or ulcerative conditions of the breast, mastitis, and breast abscess. Infants with thrush are more likely to acquire HIV from an infected mother via breast-feeding. In many low-income countries where breast-feeding is critical for infant nutrition and survival, the issue is complex and is the subject of ongoing investigation.

Pathophysiology

HIV is an enveloped, single-stranded RNA virus belonging to the family Retroviridae. It was recognized as the causative agent of AIDS within 3 years after the initial description of the syndrome in 1981, and ongoing characterization of its molecular biology has provided the identification of multiple targets for drug development. Two human immunodeficiency viruses exist: HIV-1 and HIV-2. HIV-1 has worldwide distribution, accounts for most infections outside western Africa, and is the focus of this chapter.

HIV-2 infection causes a similar clinical syndrome but is less efficiently transmitted and results in lower levels of viremia and slower progression to AIDS. A key difference in terms of management between HIV-1 and HIV-2 is that HIV-2 is naturally resistant to non- nucleoside reverse transcriptase inhibitors (see later discussion). For this reason, it is important to assess for HIV-2 by Western blot in persons who are from regions of the world where HIV-2 is present or coexists with HIV-1.

Genetic heterogeneity of HIV-1 is reflected in categorization of the virus into three groups (M, O, and N) and several clades (e.g., B, C, D, AE, CRF01_AE), some of which have overlapping geographic distribution around the world. Subtype C is prevalent in southern and eastern Africa, China, India, South Asia, and Brazil and accounts for 50% of HIV subtypes, whereas subtype B, the most common subtype in the United States, accounts for 12%.

The HIV viral genome is encoded in single-stranded RNA, packaged in core protein structures, and surrounded by a lipid bilayer envelope that is derived from the cell membrane of the host cell as the virus buds from the cell surface after replication. This outer viral membrane contains HIV-specific glycoproteins, including gp120 and gp41, which facilitate attachment and entry into host cells through interaction with the cell surface receptor, CD4, and coreceptors CCR5 and CXCR4. CD4+ helper T lymphocytes are the predominant host cell affected by HIV; this molecular tropism explains the immune system destruction manifested in chronic HIV infection and provides the rationale for clinical staging of HIV infection using CD4+ T-cell counts. The interaction of HIV with the coreceptor CCR5 led to the development of coreceptor antagonist drugs such as maraviroc.

People with genetic mutations of the CCR5 receptor are resistant to HIV infection. This helps explain how the “Berlin” patient, the man with HIV and leukemia who received a bone marrow transplant from a donor with a CCR5 mutation, was cured of HIV.

After host cell entry, the key enzyme responsible for viral replication is reverse transcriptase, an RNA-dependent DNA polymerase that is packaged within the virion core. This enzyme facilitates conversion of the HIV genome into a double-stranded DNA intermediate molecule. The second key enzymatic step is integration of this intermediate nucleic acid product into the host genome, which is facilitated by the viral protein integrase. Protein synthesis with packaging of new viral particles ensues, utilizing an HIV-specific protease. The integrase inhibitor class of drugs acts by blocking this step of integration.

Natural History

The natural history of HIV infection reflects the progressive depletion of circulating CD4+ cells, in addition to diverse effects on other immune cells and tissues that are incompletely understood. Within 1 to 4 weeks after the initial HIV infection, seroconversion may be accompanied by a nonspecific, self-limited illness, often referred to as the acute retroviral syndrome. This illness has variable manifestations but may include fever, malaise, myalgias, arthralgias, generalized lymphadenopathy, pharyngitis, and rash. The associated rash has been described as maculopapular, urticarial, or roseola-like. An illness resembling acute infectious mononucleosis syndrome, similar to that caused by Epstein-Barr virus or cytomegalovirus (CMV), and aseptic meningitis have been described. Very rarely has an acute opportunistic infection (OI) been reported in the setting of acute seroconversion. The proportion of patients experiencing such an illness is not precisely known, because many do not present to medical facilities, and for those who do, HIV infection is commonly not considered. Diagnosis of acute HIV infection requires a high index of suspicion, which does not commonly occur unless the patient reports a recent history of a high-risk exposure.

During the acute phase of infection, high levels of viremia are present (often exceeding 10 million copies per milliliter) as HIV becomes widely disseminated throughout the body and the host defenses are just beginning to counteract circulating virus through cell-mediated and humoral (antibody-mediated) immune mechanisms. Antibodies against HIV usually become detectable between 2 and 4 months after infection. The initial, high-level viremia becomes attenuated as neutralizing antibodies are established and equilibrium is reached whereby ongoing replication is partially controlled by the immune response, resulting in a steady-state level of viremia. This so-called virologic set point differs from patient to patient and is one of the determinants of the rate of disease progression. A small number of HIV-infected persons are able to control viral replication to levels below the limit of detection, and they tend to have a more benign course of disease. In these patients, designated elite suppressors by researchers, HIV replication continues to occur, and HIV RNA can be isolated from latently infected cells by means of specialized laboratory techniques.

After the establishment of HIV infection and seroconversion, a period of asymptomatic infection ensues, during which patients are free of evidence of immune suppression and OIs are uncommon. This phase of clinical latency lasts a median of 8 to 10 years, based on observational studies in the West from the pre-HAART era. Ongoing viral replication leads to gradual decline in the CD4 count.

The symptomatic stage of HIV infection can begin at any time after infection, but clinical manifestations become more likely as the CD4 count falls farther below the normal range of 800 to 1200 cells/mm3.

Both the absolute CD4 count and the percentage of CD4+ T cells correlate with the risk of developing OIs and should be monitored longitudinally to assess patients’ candidacy for prophylactic interventions and initiation of HAART. For example, Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) usually occurs in patients with a CD4 count of less than 200 cells/mm3 or a percentage of less than 10%. CMV retinitis occurs almost exclusively in patients with a CD4 count of less than 50 cells/mm3 or a percentage of less than 5%. Mucocutaneous candidiasis (oral thrush), herpes zoster, HIV-associated nephropathy, peripheral neuropathy, tuberculosis, and community-acquired bacterial pneumonia occur with increased frequency at earlier stages of infection and are less reliably predicted by CD4+  cell measurement.

Diagnosis

Diagnosis of HIV infection during the acute retroviral syndrome requires detection of circulating HIV RNA because of the absence of HIV-specific antibodies at this stage. Other laboratory findings that can raise the suspicion for acute HIV infection include a decreased total lymphocyte count; the T-cell count characteristically decreases during the first several weeks after infection and later often returns to preinfection levels, after the initial spike in viremia is brought under control by immune defenses. The erythrocyte sedimentation rate and hepatic transaminases may also be elevated. Cerebrospinal fluid pleocytosis has been documented in patients undergoing lumbar puncture in the setting of acute HIV infection.

HIV RNA can be detected by reverse transcriptase polymerase chain reaction (RT-PCR) or branched-chain DNA testing. In the acute retroviral syndrome, the VL is usually very high, and ultrasensitive RT-PCR is not generally needed. Although commercially available PCR and branched DNA tests are licensed for disease monitoring and not for diagnosis of HIV infection, their specificity is sufficiently high that finding high levels of HIV RNA in a patient with suspected acute HIV infection provides convincing evidence for infection. In all such cases, close follow-up with repeat HIV antibody testing to confirm seroconversion within 2 to 4 months is essential.

Diagnosis of HIV at all other stages of disease relies on commercially available assays for detecting HIV-specific antibodies. A standard protocol involves screening with the highly sensitive enzyme immunoassay (EIA) that detects antigens of both HIV-1 and HIV-2. Negative EIA is sufficient to rule out HIV infection, except in cases where acute HIV infection is suspected, as just described.

Positive EIA tests require further confirmation with the more specific Western blot test. The CDC has established criteria for Western blot positivity, which include the presence of at least two of the HIV- specific bands p24, gp41, and gp160/120. The Western blot is considered negative if no bands are present and indeterminate if an HIV band is present but the criteria for positivity are not met. Indeterminate Western blot results usually include a single p24 band and can occur during early infection, while seroconversion is in progress, or in advanced AIDS when antibody production is impaired. Causes of indeterminate Western blot results that are unrelated to HIV include pregnancy, autoimmune disease, and cross- reacting antibodies resulting from blood transfusion or organ transplantation.

Other HIV antibody kits have been developed for ease of administration or achievement of rapid results, and they have utility in settings such as community-based screening programs, emergency departments, and even patient-initiated home testing. OraSure, an office-based test that employs a special swab for collecting oral fluid specimens rather than blood, was licensed in 1996. Specimens are collected at the point of care and sent to a central laboratory, where antibodies are detected; the sensitivity and specificity are similar to those of traditional blood-based methods. OraQuick Advance, a rapid HIV test that can utilize whole blood, plasma, or oral fluid, was approved in 2004; OraQuick In-Home, the first over-the-counter home-use version of this test, was approved in 2012. These tests can provide results comparable in accuracy to EIA within about 20 minutes. An advantage of this technique is the ability to provide reliable negative results at the point of care or in the comfort of a patient’s home. Positive results still need to be confirmed with standard EIA and Western blot serologic testing.

Screening

The traditional paradigm for screening of asymptomatic patients for HIV has included targeting patients with behavioral risk factors for HIV transmission and patients seeking care for sexually transmitted diseases. Documentation of separate, written consent and administration of formal pretest and posttest counseling has been recommended and is still required by statute in many U.S. states.

In response to the consistent observations that many people are not diagnosed with HIV until late in the course of disease and that transmission rates for infected persons who are unaware of their serostatus are several times higher than for persons who are aware that they are infected, the CDC issued new guidelines in September 2006 to make HIV testing a routine part of medical care. Voluntary (opt-out) screening is now recommended in health care settings for all persons aged 13 to 64 years, regardless of risk. Screening should be repeated annually for persons with behavioral risk factors for HIV and should be repeated each time a person seeks treatment for symptoms related to sexually transmitted disease. The CDC advocates that requirements for separate, written consent for HIV testing are no longer needed; instead, general consent to receive medical care can be considered sufficient.

Approach to the Patient with HIV Infection

HIV care is a continuously evolving field, and new drugs and classes of drugs have been introduced in recent years. Professional guidelines for antiretroviral therapy (ART) are updated frequently as data from clinical trials are published and accumulating clinical evidence influences beliefs about best practices in HIV care. For these reasons, the receipt of appropriate care by HIV+ patients is determined in large part by the experience of the care provider. The volume of HIV+ patients seen in one’s practice is known to correlate with measures of quality care. A U.S. Department of Health and Human Services panel recommends that HIV patients receive care from a health care provider who routinely cares for at least 20 and preferably 50 HIV- infected patients. Referral to a specialist is warranted in cases of treatment failure due to drug resistance or for management of complications of HIV or antiretroviral drugs. Because of the multifaceted nature of the longitudinal care of HIV-infected patients, an interdisciplinary approach, integrated and coordinated by an experienced primary care provider, is optimal.

The initial history and physical examination of HIV-infected patients should be systematic and comprehensive, owing to the multiorgan system nature of diagnoses associated with HIV infection. A thorough review of current and recent symptoms should assess for presence of OIs and malignant or premalignant conditions. Symptoms such as unexplained weight loss, fever, chronic diarrhea, recurrent oral or genital ulcers, dysphagia, dyspnea, or gastrointestinal bleeding should prompt further investigation for the presence of undiagnosed manifestations of HIV-related complications. Because patients with HIV infection have a higher incidence of cognitive impairment, mental illness, and substance abuse than the general population, symptoms of neurocognitive impairment (e.g., impaired memory), depression, suicidality, and unhealthy alcohol and drug use should also be carefully assessed.

The past medical and surgical history should focus on conditions that may follow a more malignant course in the setting of HIV infection, such as chronic viral hepatitis, and conditions that can be exacerbated by HIV or by ART, such as cardiovascular or renal disease and metabolic abnormalities such as dyslipidemia or impaired glucose tolerance. The circumstances surrounding the patient’s HIV acquisition should be formally assessed. The provider should understand previous and current patterns of risk behaviors for the purpose of counseling regarding transmission prevention (positive prevention) and to assess the patient’s risk of acquisition of drug- resistant virus and current risk for concomitant sexually transmitted infections.

A complete physical examination should be performed at the time of initial evaluation and at subsequent visits. Signs such as temporal wasting, lymphadenopathy, and hepatomegaly or splenomegaly can provide clues to the stage of disease and alert the provider to the presence of OIs or AIDS-related malignancies. The oral cavity should be examined for the presence of thrush, oral hairy leukoplakia, and mucosal lesions of Kaposi sarcoma. A complete skin examination is important on initial evaluation and longitudinally, because many OIs and medication toxicities have cutaneous manifestations. A funduscopic examination should be done, and, in those patients with a CD4 count of less than 50 to 100 cells/mm3, referral to an ophthalmologist is necessary to screen for evidence of CMV retinitis. Close examination of the anogenital area may identify treatable sexually transmitted infections and premalignant lesions associated with human papillomavirus infection. Recommended laboratory evaluations are presented in Table 1.

Table 1

Initial Laboratory Evaluation

Test Frequency Comments
HIV antibody testing At initial visit If prior documentation is not reliable or if HIV RNA is undetectable
CD4+ T-cell count At initial visit, then every 3–6 mo Levels may be falsely elevated in splenectomized patients and with concurrent HTLV-1 infection.
Plasma HIV RNA (viral load) At initial visit, before ART initiation, every 3 mo while on ART Ultrasensitive viral load assay detects levels as low as 20 copies/mL and should be used to monitor response while on treatment.
Resistance testing At initial visit, and with treatment failure before change in ART regimen Genotype and phenotype tests are available; genotypes are more commonly used.
HLA-B*5701 testing Before treatment initiation if considering abacavir (Ziagen)
Coreceptor tropism assay Before treatment initiation if considering CCR5 antagonist (maraviroc [Selzentry])
Complete blood count At initial visit, then every 3–6 mo AZT can cause bone marrow suppression and macrocytosis.
Serum chemistry panel At initial visit Up to 75% of HIV-infected patients have elevated hepatic transaminases at diagnosis.
Fasting lipid profile and blood glucose level At initial visit Every 3–6 mo
Hepatitis screen (anti- HCV, anti-HAV, anti- HBsAg, anti-HBcAg) At initial visit HAV, HBV vaccinations are indicated for nonimmune patients.
Syphilis serology At initial visit and annually in sexually active patients Confirm with FTA-ABS test if positive; up to 6% of HIV-infected patients have biologic false-positive RPR result.
Urine NAAT for gonorrhea and Chlamydia* Consider at initial visit and annually in sexually active patients Testing every 3–6 mo is recommended for very-high- risk patients.
Toxoplasma gondii

serology

At initial visit and if CD4+ count is <100 cells/mm3 Most cases of toxoplasmosis represent reactivation of latent infection.
Tuberculin skin test (PPD) At initial visit, then annually in high-risk persons (e.g., homeless, injection drug users) if initial test is negative Cutoff of >5 mm of induration is indication for treatment of LTBI.
PAP smear† At initial visit Annually
G6PD screen At initial visit Identifies patients at risk for hemolysis induced by dapsone or primaquine
Chest radiograph If patient has pulmonary symptoms or a positive PPD result Not recommended routinely

Abbreviations: ART = antiretroviral therapy; AZT = azidothymidine (zidovudine); FTA-ABS = fluorescent treponemal antibody, absorbed; G6PD = glucose-6-phosphate dehydrogenase; HAV = hepatitis A virus; HBcAg = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HLA = human leukocyte antigen; HTLV-1 = human T- lymphotropic virus 1; LTBI = latent tuberculosis infection; NAAT = nucleic acid amplification test; PAP smear = Papanicolaou test; PPD = purified protein derivative; RPR = rapid plasma reagin test.

*  Consider rectal and oral screening.

†  Consider anal PAP smear, particularly in  MSM.

Antiretroviral Therapy

Antiretroviral drugs that are currently approved for the treatment of HIV fall into six classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, integrase inhibitors, and chemokine (CC) receptor 5 (CCR5) antagonists (Table 2). The goals of therapy are to increase disease-free survival, achieve maximal and sustained suppression of viral replication to undetectable levels (<48 copies), preserve immunologic function, and improve quality of life.

Table 2

Approved Antiretroviral Medications

 

Abbreviations: ART = antiretroviral therapy; CNS = central nervous system; CPK = creatine phosphokinase; CYP3A = cytochrome P-450 isoenzyme 3A; GI = gastrointestinal; HLA = human leukocyte antigen; MI = myocardial infarction; PPI = proton pump  inhibitor.

† A new fixed-dose combination pill known as the Quad pill, which contains cobicistat, a novel pharmacologic booster that has no anti-HIV activity, along with tenofovir, emtricitabine, and a novel integrase inhibitor elvitegravir, has been approved for use in the United  States.

When to Initiate Antiretroviral Therapy

In the mid-1990s, when combination HAART became available, the treatment paradigm was to “hit early and hit hard,” because it was believed that the virus could be eradicated with treatment and rapid immune restoration could be achieved. However, as more data accumulated, there was recognition that the virus establishes itself within hours after infection and cannot be eradicated with HAART. In addition, during this early HAART era, it was observed that several of the regimens used were complicated, were associated with several toxicities and reduced quality of life, and, importantly, were not associated with marked clinical benefits. Therefore, between 1996 and 2006, the recommended CD4 count threshold for starting therapy steadily declined, with 2006 recommendations of the U.S. Department of Health and Human Services (DHHS), the International AIDS Society–USA, and the British HIV Society all generally indicating a threshold of 200 cells/mm3 for initiation of treatment in asymptomatic patients.

More recently, however, accumulating evidence of the beneficial effects of earlier versus later treatment has resulted in a shift toward earlier initiation of HAART. There are now several classes of drugs, and many of the newer ART regimens are more potent, better tolerated, and less complex than before (i.e., low pill burden and once- daily dosing). The newer regimens, such as PIs boosted with ritonavir (Norvir) and NNRTIs used in triple-drug combinations, are more effective at achieving and sustaining virologic suppression (HIV-1 RNA <20–400 copies, depending on the assay used) than the older regimens that used unboosted PIs and NRTIs. Most cases of virologic failure now occur when patients are lost to follow-up, are nonadherent, or discontinue their treatment. Furthermore, there is mounting evidence from several cohorts with long-term follow-up of HIV-infected patients that demonstrates a benefit of starting ART earlier. Consistently, persons starting treatment at a CD4 count threshold below 200 cells/mm3 have a two to four times greater risk of AIDS or death than patients who start when their CD4 count is between 201 and 350 cells/mm3.

There is also increasing recognition of the importance of non–AIDS- defining illnesses, such as cardiovascular, renal, and liver disease, at higher CD4 counts (>350 cells/mm3). Cohort data (e.g., North American AIDS Cohort Collaboration on Research and Design [NA- ACCORD], ART-Collaborative) and one large trial (Strategies for Management of Anti-Retroviral Therapy [SMART]) reported significant benefits in reducing these complications when ART was initiated at higher CD4 thresholds (>350 or >500 cells/mm3). Earlier initiation of HAART also appears to be associated with reduced risk of transmission, greater preservation of the R5-tropic virus, and improved immune restoration (including CD4 counts); it also may be cost-effective.

Current Recommendations for Antiretroviral Therapy

Current guidelines for HIV treatment in the United States are shown in Tables 3 and 4. Current U.S. guidelines advocate offering ART to all patients with HIV, regardless of CD4 count. The strength of the recommendation, however, is still stratified by CD4 count, as shown in Table 2. ART has also been shown to reduce the risk of HIV transmission to uninfected partners and may be offered in this scenario as well. Current guidelines recommend considering individualized treatment for specific scenarios such as active hepatitis B co-infection or pregnancy. Critical to all these recommendations, however, is ensuring that the patient is ready to start therapy and understands the regimen, the importance of adherence to it, and the need to continue therapy for life.

Table 3

U.S. DHHS Guidelines for Initiation of HIV Treatment, 2012

From U.S. DHHS Guidelines, 2012. Available at http://www.aidsinfo.nih.gov/Guidelines/ (accessed July 9, 2015).

* Strength of Recommendations: A = strong evidence to support the recommendation; B = moderate evidence to support the recommendation. Quality of Evidence: I = randomized trials with either clinical or validated laboratory outcomes (e.g., viral load); II = nonrandomized trials or well-designed observational cohort studies with long-term clinical outcomes; III = recommendation based on expert  opinion.

† Patient should be willing to commit to treatment and should understand the benefits and risks of therapy and the importance of  adherence.

Table 4

International AIDS Society (IAS)-USA Guidelines for Initiation of HIV Treatment, 2012

From Thompson MA, Aberg JA, Hoy J, et al. Antiretroviral treatment of adult HIV infection: 2012 Recommendations of the International AIDS Society-USA Panel. JAMA 2012;308:387– 402.

* Strength of Recommendations: A = strong evidence to support the recommendation; B = moderate evidence to support the recommendation; C = limited support for the recommendation. Quality of evidence: Ia = evidence from one or more randomized controlled clinical trials published in the peer-reviewed literature; Ib = evidence from one or more randomized clinical trials presented in abstract form at peer-reviewed scientific meetings; IIa = evidence from nonrandomized clinical trials or cohort or case-control studies published   in peer-reviewed literature; IIb = evidence from nonrandomized clinical trials or cohort or case- control studies presented in abstract form at peer-reviewed scientific meetings; III = recommendation based on the panel’s analysis of the accumulated available   evidence.

†  May delay ART initiation until after completion of HCV treatment if CD4  >500.

Selection of an Antiretroviral Regimen

Table 5 presents the regimens recommended for ART initiation in treatment-naive HIV-1–infected adults residing in the United States and other high-income countries. Current ART strategies that represent the standard of care are based on combining at least three potent antiretroviral agents. Therapy is individualized in high-income settings and takes into account several factors such as comorbidities, concomitant medications, possible drug interactions, pill burden, dosing schedule, adherence issues, risk for side effects, and pregnancy. Triple-NRTI regimens are inferior to PI- and NNRTI- containing regimens and therefore are not recommended.

Table 5

Starting Regimens for Antiretroviral Naive Patients*

 

From U.S. DHHS Guidelines, 2012. Available at http://www.aidsinfo.nih.gov/Guidelines/ (accessed July 9, 2015).

Abbreviations: 3TC = lamivudine (Epivir); ABC = abacavir (Ziagen); ABC/3TC = abacavir/lamivudine (Epzicom); ATV = atazanavir (Reyataz); DRV = darunavir (Prezista);   EFV = efavirenz (Sustiva); FPV = fosamprenavir (Lexiva); FTC = emtricitabine (Emtriva); INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir (Kaletra); NNRTI = non- nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; r = ritonavir (Norvir); RAL = raltegravir (Isentress); RPV = rilpivirine (Edurant); TDF = tenofovir (Viread); TDF/FTC = tenofovir/emtricitabine (Truvada); ZDV = zidovudine (Retrovir); ZDV/3TC = zidovudine/lamivudine  (Combivir).

* Select one component from Column A (dual NRTI combination) and one from Column B (NNRTI, PI, or INSTI).

† ZDV/3TC plus LPV/r is the preferred regimen for pregnant women only (double LPV/r dose in pregnancy).

Efavirenz (Sustiva) is the preferred NNRTI because it has the best long-term treatment response to date, based on clinical trial data. It is available with tenofovir (Viread) and emtricitabine (Emtriva) in a coformulation, called Atripla (efavirenz 600 mg + tenofovir 300 mg + emtricitabine 200 mg), that can be taken once a day. Nevirapine (Viramune) is an alternative NNRTI; it should not be used in women with a CD4 count of less than 250 cells/mm3 or in men with less than 400 cells/mm3, because it is associated with increased risk of severe hepatotoxicity in such patients. Newer NNRTIs include etravirine (2007) and rilpivirine (2011). Rilpivirine (Edurant) is also available in a daily coformulation with tenofovir and emtricitabine called Complera (rilpivirine 25 mg + tenofovir 300 mg + emtricitabine 200 mg). Some but not all resistance mutations that develop on efavirenz and nevirapine can confer resistance to the newer NNRTIs. Therefore it is important to review the specific genotypic mutations and consult HIV experts/resources before deciding if an antiretroviral combination can be expected to be effective. Furthermore, patients initiating treatment with rilpivirine at viral loads greater than 100,000 have a higher risk of virologic failure. Efavirenz-based regimens are equivalent to boosted- PI regimens in terms of efficacy and durability but have the advantages of low pill burden and limited long-term toxicity. The main drawback to NNRTI-containing regimens is their low barrier to resistance; for this reason, NNRTIs are less favored in patients for whom adherence is likely to be a problem.

The preferred PIs are the newer ones: atazanavir (Reyataz) boosted with ritonavir, and darunavir (Prezista) boosted with ritonavir. They are potent, have a high genetic barrier to resistance, and can be dosed once daily in many treatment-naive patients. The main drawbacks with PIs as a class are their interactions with other drugs, gastrointestinal intolerance, and metabolic complications (for most members of the class). The relative advantages and disadvantages of initial ART regimens are shown in Table 6. Note that while RAL is the only integrase inhibitor recommended in initial ARV regimens, there is a daily quadruple combination pill (Stribild), which includes elvitegravir, a newer integrase inhibitor, along with cobicistat, emtricitabine, and tenofovir.

Table 6

Advantages and Disadvantages of Initial Antiretroviral Regimens

 

Abbreviations: 3TC = lamivudine (Epivir); ABC = abacavir (Ziagen); ADR = adverse drug reaction; ATV = atazanavir (Reyataz); ddI = didanosine (Videx); d4t = stavudine (Zerit); DRV = darunavir (Prezista); EFV = efavirenz (Sustiva); FPV = fosamprenavir (Lexiva); FTC = emtricitabine (Emtriva); INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir (Kaletra); NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine (Viramune); PI = protease inhibitor; r =   ritonavir (Norvir); RAL = raltegravir; RPV = rilpivirine; TDF = tenofovir (Viread); VL = viral load; ZDV = zidovudine (Retrovir).

* FTC and 3TC are similar except for convenience of coformulations; FTC has longer intracellular half-life and less extensive  experience.

† In hepatitis B virus (HBV) co-infection (HBV surface antigen positive), hepatitis B flare may be caused by discontinuation of agent or by HBV resistance to NRTI (3TC, FTC,   TDF).

Monitoring Response to Antiretroviral Therapy

After ART is initiated, the CD4 count usually increases within a few weeks, largely because of redistribution of cells. Subsequently, the CD4 count improves over years of therapy, at an average rate of 100 cells/mm3 per year, and then reaches a plateau. The starting CD4 count appears to influence the plateau reached (i.e., people starting at a lower count also plateau at a lower count than do those whose baseline count was higher). In approximately 5% to 10% of individuals, the CD4 response is less than this or does not increase from baseline. This is not evidence of treatment failure if the VL is undetectable. The plasma HIV VL rapidly decreases after initiation of HAART, and by 4 weeks most patients have at least a 1 log10 drop in VL. In most individuals, it should become undetectable (<50 copies/mL) by 24 weeks.

The CD4 count should be assessed at 3 months after ART initiation and then every 3 to 6 months thereafter. The VL should be measured 2 to 8 weeks after ART initiation, every 1 to 2 months until undetectable, and thereafter every 3 to 4 months. If a patient has been on a long-term stable suppressive regimen, visits can be reduced to every 6 months, with VL and CD4 testing performed at that interval. If a change in ART is motivated by drug toxicity or regimen simplification, it is recommended that VL be measured 2 to 8 weeks afterward, to confirm potency of the new regimen.

Other laboratory tests and their frequency of monitoring are shown in Table 1.

Treatment Failure

Treatment failure can be virologic, immunologic, or clinical. Virologic failure is defined as failure to achieve a VL of less than 400 copies/mL by 24 weeks or less than 50 copies/mL by 48 weeks, or a consistent finding (two consecutive measurements) of more than 50 copies/mL after a fall to less than 20–50 copies/mL at 48 weeks. Most patients should have a decrease of at least 1 log10 in VL within 4 weeks.

Immunologic failure is the failure to increase the CD4 count by 25 to 50 cells/mm3 during the first year. In treatment-naive patients, current regimens are associated with an average increase of 150 cells/mm3 in the first year. Clinical failure is the occurrence or recurrence of HIV-related events 3 months or longer after HAART initiation; this is not to be confused with immune reconstitution syndromes (discussed later).

Today, with the use of appropriate combinations, newer fixed-dose formulations, and more tolerable regimens, treatment failure in patients on their first-line therapy usually occurs because of inadequate adherence or treatment discontinuation (e.g., loss to follow-up, intolerance) rather than regimen inefficacy. Occasionally, pharmacokinetic issues such as a reduced drug level due to genetic polymorphism or a drug interaction (e.g., omeprazole [Prilosec] with atazanavir [Reyataz]) or transmitted resistance can be causes of treatment failure. In the United States, the CDC recently reported that 16% of newly diagnosed HIV-positive people without prior ART use had evidence of ART resistance.

Drug Resistance and Resistance Testing

A patient may be infected with a drug-resistant HIV virus to begin with (primary resistance), or, more commonly, resistance can emerge as a result of treatment (secondary resistance).

Several NNRTI-associated resistance mutations confer resistance to other NNRTIs, including Y181C. However, K103N and 106M mutations, which cause resistance to efavirenz and nevirapine, do not confer resistance to newer-generation NNRTIs such as etravirine and rilpivirine.

Among NRTIs, the resistance mutation most commonly detected when regimens containing lamivudine (Epivir) or emtricitabine are used is M184V. This mutation also makes the virus hypersusceptible to tenofovir or zidovudine (Retrovir), so in many situations lamivudine or emtricitabine may be kept in the regimen if tenofovir or zidovudine is being used. Other NRTIs can be associated with thymidine analogue mutations, or TAMS (e.g., 41L, 210W, 215Y); accumulation of TAMS or presence of multinucleoside mutations (e.g., Q151M, T69 insertion) confers cross-resistance to other NRTIs.

With PIs, accumulation of mutations generally leads to significant cross-resistance. Ritonavir-boosted PIs, particularly lopinavir (i.e., Kaletra) and darunavir, have high barriers to resistance, so development of resistance does not occur as easily as with the NNRTI class. Indications for resistance testing include the baseline resistance (prior to initial therapy), acute HIV infection, suboptimal viral suppression (VL >1000 copies/mL), and virologic failure with VL greater than 1000 copies/mL. Resistance testing should be performed while the patient is on therapy or within 1 month after discontinuation, because, after that point, the wild-type virus may reemerge and predominate.

Current standard methods of genotyping do not detect minority variants (resistant virus populations accounting for <10% to 20% of plasma virus). Resistance testing is usually a genotypic test and should be performed early in cases of virologic failure. The phenotypic resistance assay is more expensive and is typically used in patients who have multiple resistance mutations after multiple virologic failures. Interpretation of resistance testing should include adherence assessment, prior history of antiretroviral agents, and prior resistance testing results, because a history of resistance mutations remains relevant even if they are not detected on the current resistance test. Because resistance testing interpretation is complex, special expertise should be sought.

Adverse Drug Reactions and Drug- Drug Interactions

Adverse drug reactions (ADRs) are common with ART and are a reason for patient nonadherence or treatment discontinuation. ADRs can be idiosyncratic, dose related, time related (delayed), or dose and time related (cumulative). A particular ADR may be drug specific (e.g., hypersensitivity to abacavir [Ziagen]) or class related (e.g., hyperlipidemia because of PIs). It is important to inform patients of potential common or serious ADRs associated with their therapy.

Often, the challenge in managing ADRs is that the patient is taking several concomitant medications that may have overlapping toxicities and ADR profiles. A symptom-based approach is often most practical (Table 7). Although many of the ADRs can be managed conservatively, some, such as symptomatic lactic acidosis, systemic hypersensitivity reactions, Stevens-Johnson syndrome, acute pancreatitis, and severe hepatotoxicity, are potentially life threatening. Serious ADRs necessitate withdrawal of the offending drug, and rechallenge with the drug should not be attempted in these situations.

Table 7

Approach to Adverse Drug Reactions in the HIV-Infected Patient*

 

Based on Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, U.S. Department of Health and Human Services, March  2012.

Abbreviations: 3TC = lamivudine (Epivir); ABC = abacavir (Ziagen); ALT = alanine aminotransferase; ATV = atazanavir (Reyataz); BMI = body mass index; CD4 = CD4+ T-cell count (in cells/mm3); d4T = stavudine (Zerit); ddC = zalcitabine (Hivid)2; ddI = didanosine (Videx); DM = diabetes mellitus; DRV = darunavir (Prezista); EFV = efavirenz (Sustiva);   ETR = etravirine (Intelence); FPV = fosamprenavir (Lexiva); FTC = emtricitabine (Emtriva); GI = gastrointestinal; HBV = hepatitis B virus; HLA = human leukocyte antigen; IDV = indinavir (Crixivan); LPV/r = lopinavir/ritonavir (Kaletra); MVC = maraviroc (Selzentry); NARTI = nucleoside reverse transcriptase inhibitor; NCEP = National Cholesterol Education Program; NFV = nelfinavir (Viracept); NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine (Viramune); PI = protease inhibitor; r = RTV as a booster; RTV = ritonavir (Norvir); SJS = Stevens-Johnson syndrome; SQV = saquinavir (Invirase); TDF = tenofovir (Viread);  TEN = toxic epidermal necrolysis; TPV = tipranavir (Aptivus); ZDV = zidovudine   (Retrovir).

1  Not FDA approved for this indication.

2  Not available in the United States.

7  Available as dietary supplement.

* Only common and serious side effects are dealt with; side effects such as osteoporosis, avascular osteonecrosis (PIs), unconjugated hyperbilirubinemia, retinoid-like effects (IDV), and cranial malformations (EFV) are also known to  occur.

† Approximately 0.3%–1% with NVP; a low dose lead-in period for NVP may decrease the risk; less common (0.1%) with EFV; occurs in the initial weeks after initiation; safety of replacing NVP with another NNRTI is unknown.

‡ Approximately 5% with ABC; once-daily dosing possibly increases the risk; if ABC-related, symptoms resolve within 48 h after discontinuation of  ABC.

§ FPV and TPV are sulfonamide derivatives; potential cross-hypersensitivity with sulfonamides.

¶  Symptoms begin with first doses; may abate with  time.

# Low-dose lead-in period for NVP may reduce the risk; onset within the first few weeks with NNRTIs, after weeks to months with PIs, and after months to years with NRTIs; discontinuation of 3TC, FTC, or TDF in HBV co-infected patients may cause acute flare-up of hepatitis; safety of replacing NVP with another NNRTI is  unknown.

** Class-specific adverse effect of NRTIs, because of mitochondrial toxicity; do not combine ddI/d4T/ddC; ABC, 3TC, and TDF are less prone; all four syndromes can occur in variable combinations; symptomatic lactic acidosis is rare but is associated with high   mortality.

†† Approximately 10% of patients taking IDV experience at least one episode of colic; occurrence is seen in only 50%, if fluid intake is improved (at least 1.5–2 L of noncaffeinated fluid, preferably water).

‡‡ Almost all ZDV-treated patients have isolated macrocytosis; anemia and neutropenia occur in approximately 1%–4% and 2%–8%,  respectively.

§ Occurs during initial weeks of treatment; patients are to be warned to restrict risky  activities.

¶¶ Only atorvastatin (Lipitor) and pravastatin (Pravachol) among statins, and gemfibrozil (Lopid) and fenofibrate (Triglide) among fibrates, can be coadministered with  PIs.

Numerous important drug-drug interactions exist among antiretroviral agents and other medications of various classes. Familiarity with common interactions and ready access to reliable HIV pharmacology reference materials or a clinical pharmacologist with expertise in ART is essential for the clinician prescribing ART. Table 8, although not exhaustive, lists important drug-drug interactions, including combinations that are contraindicated and those that require adjustments to prescribe dosages. Tables 9 and 10 show dose adjustments that must be made with coadministration of certain antiretroviral drugs.

Table 8

Drug Interactions with Antiretroviral Agents*

 

Adapted from John G. Bartlett’s Pocket Guide to Adult HIV/AIDS Treatment 2008-2009. Fairfax, VA, Johns Hopkins HIV Care Program,  2008.

Abbreviations: ATV = atazanavir (Reyataz); EFV = efavirenz (Sustiva); NFV = nelfinavir (Viracept); NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine (Viramune); PI = protease inhibitor; RTV = ritonavir (Norvir).

2  Not available in the United States.

7  Available as dietary supplement.

* Delavirdine (Rescriptor) drug interactions are not shown as this drug is no longer used in clinical practice. Detailed information about drug interactions and searchable drug interaction databases are available at http://www.hopkins-aids.edu/, http://www.hiv-druginteractions.org/, http://hivinsite.ucsf.edu.

Table 9

Combinations Requiring Dose Adjustments: NRTIs

Adapted from John G. Bartlett’s Pocket Guide to Adult HIV/AIDS Treatment 2008–2009. Fairfax, VA, Johns Hopkins HIV Care Program,  2008.

Abbreviations: AUC = area under the concentration-versus-time curve; CBC = complete blood count; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; EC = enteric coated; NRTI = nucleoside reverse transcriptase  inhibitor.

Table 10

Combinations Requiring Dose Adjustments: PIs and NNRTIs

Adapted from John G. Bartlett’s Pocket Guide to Adult HIV/AIDS Treatment 2008–2009. Fairfax, VA, Johns Hopkins HIV Care Program,  2008.

Abbreviations: NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; SD = standard dose; TDM = therapeutic drug  monitoring.

Hepatitis C Co-infection

As shown in Table 1, screening for Hepatitis C virus (HCV) is recommended in all HIV-positive patients. Co-infected individuals, especially those with low CD4 counts (≤350 cells/mm3), are three times more likely to progress to cirrhosis and liver failure than those with HCV mono-infection. Treatment of HCV can slow the progression of liver disease. Until recently, however, the combination of peginterferon and ribavirin (PegIFN/RBV) was the only available treatment option for HCV, but it was poorly tolerated because of adverse drug effects. Now there are new HCV protease inhibitors such as boceprevir (BOC) and telaprevir (TVR) that have revolutionized treatment of HCV. These newer medications, however, can interact with antiretrovirals.

Clinicians may defer HCV treatment in HIV-positive patients with no or minimal liver fibrosis. In that case, the recommended initial antiretroviral therapy for co-infected patients is the same as those with HIV alone (see Table 5). If treatment for both HCV and HIV is to be done simultaneously, careful consideration should be paid to potential drug–drug interactions. If a patient is receiving a RAL-based ARV regimen, either BOC or TVR can be used. If using an ATV/r or EFV-based regimen, TVR can be used, but the TVR dose must be increased to 1125 mg every 7 to 9 hours if prescribed with EFV. Neither BOC nor TVR is safe to use with DRV/r. The treatment of HCV is evolving rapidly, so management of HIV-HCV co-infected patients is likely to change markedly in the coming years.

Complications

Diagnosis and Management of Opportunistic Infections

OIs are the most common cause of disability and death in patients who are not receiving ART. Clinical experience from the pre-HAART era demonstrated that the risk of OIs increases proportionately with the severity of immune system dysfunction and can be roughly predicted by the CD4 count in patients receiving and not receiving HAART. Guidelines for initiating and discontinuing antimicrobial prophylaxis against OIs are based on the CD4 count, as summarized in Table 11.

Table 11

Antimicrobial Prophylaxis for Opportunistic Infections

Abbreviations: CD4 = CD4+ T-cell count (in cells/mm3); DS = double-strength; HAART = highly active antiretroviral therapy; IgG = immunoglobulin G; LTBI = latent tuberculosis infection;   SS = single-strength; TMP-SMX =  trimethoprim-sulfamethoxazole.

1  Not FDA approved for this indication.

3  Exceeds dosage recommended by  manufacturer.

Diagnosis of OIs requires that clinicians recognize that a diverse array of bacterial, fungal, viral, and parasitic pathogens can cause overlapping clinical syndromes. A broad differential diagnosis must be considered when evaluating an HIV-infected patient with specific or generalized symptoms. Aside from infectious complications, symptoms may arise from toxicities inherent to antiretroviral or other medications. Patients infected with HIV have increased rates of cardiovascular, renal, and hematologic abnormalities, which may also cause nonspecific symptoms. A syndromic approach to recognizing complications of HIV infection is described in the following paragraphs. Recommended treatment regimens for the most common OIs are presented in Table 12. Detailed treatment guidelines that are periodically updated are available from the CDC and the HIV Medicine Association of the Infectious Diseases Society of America (http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf [accessed July 9, 2015]).

Table 12

Recommended Treatment for Opportunistic Infections

 Abbreviations: A-a gradient = alveolar-arterial difference in partial pressure of oxygen (PaO2  − PaO2 ); ART = antiretroviral therapy; CD4 = CD4+ partial pressure of oxygen.

1  Not FDA approved for this indication.

T-cell count (in cells/mm3); PaO  =  arterial

Neurologic Complications

Both central nervous system disease and peripheral nerve abnormalities are common in advanced AIDS. Peripheral neuropathy has been associated with some NRTI medications, most commonly stavudine (d4T, Zerit), as a result of the mitochondrial toxicity inherent to these drugs. HIV infection can directly cause distal sensory neuropathy, which may manifest as dysesthesia or hypersensitivity, decreased reflexes, and chronic neuropathic pain. Inflammatory demyelinating polyneuropathy (e.g., Guillain-Barré syndrome), which has known associations with some enteric pathogens, causes ascending motor weakness, typically without sensory involvement.

CMV infection may cause polyradiculopathy, transverse myelitis, and encephalitis/ventriculitis in patients with CD4 counts lower than 50 cells/mm3. CMV end-organ disease, including retinitis (a vision- threatening condition), requires prompt diagnosis and initiation of appropriate anti-CMV therapy.

Focal central nervous system lesions may be caused by infectious and malignant conditions. Cerebral toxoplasmosis usually occurs in patients with prior exposure to Toxoplasma gondii who develop reactivation disease when the CD4 count is lower than 100 cells/mm3. The main differential diagnosis for one or several enhancing brain lesions includes toxoplasmosis and primary central nervous system lymphoma (PCNSL). PCNSL is almost always associated with

Epstein-Barr virus, and detection of nucleic acid for Epstein-Barr virus in cerebrospinal fluid carries a high specificity for this condition in the proper radiographic context. Progressive multifocal leukoencephalopathy, a rare and potentially devastating demyelinating condition, is caused by reactivation of JC virus and can manifest as focal neurologic deficit, seizures, or cognitive dysfunction. Cryptococcus neoformans is a common cause of meningitis in AIDS patients and can also manifest with central nervous system mass lesions, pulmonary disease, or gastrointestinal disease. Worldwide, tuberculosis accounts for a large proportion of HIV-associated meningitis; less commonly, it can manifest as single or multiple focal lesions (tuberculomas). Neurosyphilis should be considered in patients with unexplained neurologic disease and sexual risk factors.

Respiratory Complications

Respiratory illnesses are among the most common causes of morbidity in HIV patients. Community-acquired bacterial pneumonia occurs at a significantly higher rate in HIV-infected compared with HIV- noninfected hosts, regardless of CD4 count, and is one of the most common reasons for hospitalization. Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) manifests with fever, cough, and dyspnea. Findings on physical examination and chest radiography can be variable, making the diagnosis difficult in the absence of high clinical suspicion. Elevated lactate dehydrogenase and oxygen desaturation with ambulation can be diagnostic clues. More than 90% of cases occur among patients with CD4 counts lower than 200 cells/mm3. The diagnosis is established by visualization of organisms in induced sputum (sensitivity, 50%–90%) or in bronchoalveolar lavage specimens (sensitivity, 90%–99%), most commonly with the use of immunofluorescent staining. Slight worsening of clinical symptoms after initiation of treatment for PCP is common, particularly when adjunctive corticosteroids are not administered.

The risk of reactivation of latent TB is increased 100-fold in patients with HIV infection. HIV+ persons who are latently infected have a 10% annual risk of developing symptomatic tuberculosis, compared with a 10% lifetime risk among the general population. The risk of reactivation increases with decreasing CD4 count, and patients with counts lower than 350 cells/mm3 are more likely to have atypical radiographic presentations, including middle- and lower-lobe infiltrates without cavitation. Patients with very low CD4 counts are more likely to have extrapulmonary tuberculosis. Diagnostic approaches to tuberculosis are similar in HIV+ and HIV− patients.

Tuberculin skin testing can still be used to diagnose latent tuberculosis infection, although the recommended cutoff for a positive test is 5 mm of induration. Treatment of co-infection with Mycobacterium tuberculosis and HIV requires consultation with experienced clinicians and pharmacists because of extensive drug- drug interactions among antiretroviral drugs and rifamycins.

Gastrointestinal Complications

Diagnosis of OIs affecting the gastrointestinal tract is made difficult by the numerous infections and complications of therapies that can result in nonspecific syndromes such as nausea, vomiting, abdominal pain, and diarrhea. Oropharyngeal candidiasis (thrush) commonly manifests as white plaques on the tongue, palate, or buccal mucosa that are painless and can easily be scraped off. Although thrush is typically uncomplicated and easily treatable with topical preparations such as nystatin (Mycostatin) and clotrimazole (Mycelex troches), in the proper clinical setting it can alert the clinician to the presence of esophageal candidiasis. Esophageal involvement should be suspected in patients with dysphagia and odynophagia; retrosternal chest pain may also be present. Thrush is usually present but is not required for the diagnosis, which is often made on clinical grounds rather than being confirmed with endoscopy. Patients with esophageal candidiasis typically respond after several days of treatment, and 7 to 14 days of antifungal therapy is usually sufficient. For cases not responsive to empiric treatment for candidiasis, referral for endoscopy should be considered. Esophagitis caused by CMV or herpes simplex virus requires a histopathologic diagnosis.

Acute diarrhea, defined as three or more loose or watery stools per day for 3 to 10 days, is common among HIV+ patients, and more than 1000 different enteric pathogens have been described. Data from a large cohort indicate that the most common pathogens isolated are Clostridium difficile, Shigella spp., Campylobacter jejuni, Salmonella spp., Staphylococcus aureus, and Mycobacterium avium-intracellulare (MAI).

Culture of the stool can yield a microbiologic diagnosis in many cases, particularly for acute diarrheal illnesses caused by Campylobacter, Yersinia, Salmonella, and Shigella species. Infection with C. difficile, the most common bacterial enteric pathogen in the United States for both HIV-infected and HIV-uninfected persons, is diagnosed in most settings by detection of cytotoxin in the stool by EIA or PCR, although the more laborious tissue culture is considered the gold standard.

Enteric viruses are present in 15% to 30% of HIV-infected persons with acute diarrhea. Definitive diagnosis is not feasible in most clinical laboratories; viral enteritis should be suspected in the setting of community outbreaks, because of the high transmissibility of viral pathogens. Treatment is supportive with fluid resuscitation and antimotility agents.

Chronic diarrhea (duration >30 days) was a common manifestation of advanced-stage AIDS in the pre-HAART era and is still considered an AIDS-defining condition. Most pathogens that cause acute gastroenteritis can also cause chronic symptoms. Pathogens that should be suspected in cases of chronic watery diarrhea include protozoa such as Cryptosporidium parvum, Isospora belli, and Microsporidia spp. These entities are self-limited in the absence of severe immunosuppression. In advanced HIV, pathogen-specific antimicrobial therapy is infrequently effective, and symptoms commonly do not improve without immune reconstitution in response to ART. Giardia lamblia causes watery diarrhea, abdominal bloating, and occasionally malabsorption syndrome and can occur at any CD4 count. CMV infection can affect any segment of the gastrointestinal tract and is a common cause of chronic diarrhea.

Diagnosis of gastrointestinal CMV disease is difficult without biopsy. Detection of CMV viremia with PCR does not correlate well with presence of CMV disease in HIV-infected patients, and CMV can be undetectable in serum in patients with extensive gastrointestinal disease.

Other Conditions

Mycobacterium avium and Mycobacterium intracellulare are closely related mycobacteria that are ubiquitous in the environment. They are discussed as a single pathologic entity and referred to as MAI or Mycobacterium avium complex (MAC). MAI is a common cause of chronic pulmonary disease in patients with structurally abnormal airways. In advanced HIV infection, it can cause a multiorgan system disease characterized by fever, night sweats, diarrhea, and abdominal pain. Infiltration of the bone marrow and liver may occur, leading to hematologic abnormalities and abnormal liver function tests, which can be a clue to the diagnosis. Biopsy of a lymph node or of bone marrow is sometimes necessary to diagnose disseminated MAI, but it is most often diagnosed by means of blood culture using specialized culture media.

Immune Reconstitution Inflammatory Syndrome

Recovery of cellular and humoral immune system function in response to ART is occasionally associated with severe symptoms resulting from inflammatory responses directed against opportunistic pathogens. Risk factors for this immune reconstitution inflammatory syndrome (IRIS) include a low nadir CD4 count, a high baseline VL, and PI-containing HAART regimens. Most cases of IRIS occur within the first 2 months after initiation of HAART, and onset can occur as early as within the first week. Disseminated MAI accounts for up to one third of the cases of IRIS in the United States. Other important causes of IRIS are tuberculosis, CMV infection, viral hepatitis, and candidal infections. It may be possible to decrease the risk of IRIS by delaying initiation of HAART by several weeks, until therapy for OIs has been instituted, but the risks of other complications of untreated AIDS often outweigh any potential benefit of this strategy. When it occurs, IRIS usually can be managed with nonsteroidal antiinflammatory drugs or corticosteroids. HAART should not be interrupted except in life-threatening illnesses.

Management of HIV in Pregnant Women

Periodically updated guidelines for the treatment of HIV in pregnancy are available on the U.S. Department of Health and Human Services AIDSinfo website (http://www.aidsinfo.nih.gov [accessed July 9, 2015]). Pregnancy is not known to have an effect on HIV progression. HIV progression has been shown to increase rates of preterm delivery and low birth weight in developing countries, but this link has not been established in resource-rich settings. All pregnant women should be offered HAART to reduce perinatal transmission and improve maternal health, regardless of CD4 count or VL. Guidelines for ART are otherwise similar for pregnant and nonpregnant patients, with the important exception that drugs with unacceptable or inadequately studied safety profiles should be avoided. Didanosine (Videx) and stavudine should be avoided. Earlier, efavirenz use during pregnancy was not recommended. Recent guidance, however, suggests that efavirenz can be continued safely in women already on efavirenz- based regimens, as long as the patient is virologically suppressed on that regimen. In fact, as of 2012, the British HIV association’s guidelines no longer prohibit the use of efavirenz in pregnancy. If possible, preferred regimens should include zidovudine and lamivudine with lopinavir/ritonavir (Kaletra). Data suggest that nevirapine (Viramune) should be avoided in women who have CD4 counts higher than 250 cells/mm3 at the time of initiation of therapy.

This recommendation does not pertain to the practice of giving a single dose of nevirapine in the intrapartum period in resource-poor settings to prevent perinatal transmission. Elective cesarean should be offered at 38 weeks’ gestation to women who are likely to have VLs greater than 1000 copies/mL at the time of delivery. After delivery, infants born to HIV-infected mothers who were not on antepartum ARVs should receive zidovudine for 6 weeks and 3 doses of nevirapine (at birth, at 48 hours, and 96 hours after the second dose).

Pre-exposure Prophylaxis (PrEP) of HIV Infection

Despite community and behavioral interventions, new HIV infections continue to occur, with the highest rates among MSM and Black/African men and women. In 2010, the iPrEx trial showed that daily oral tenofovir disoproxil fumarate 300 mg (TDF) with emtricitabine 200 mg (FTC) was both safe and efficacious in the prevention of incident HIV infections in MSM. Now, several trials have substantiated the findings of the iPREX trial in other high risk populations, including IVDUs and high-risk heterosexual people. The FDA approved TDF/FTC for the prevention of HIV infection among all adults in July 2012. The CDC has issued interim guidance for clinicians while formal guidelines are in process. Before initiating PrEP, a patient should (1) have a documented HIV-negative status; (2) have a substantial ongoing risk of becoming infected with HIV, either through sexual contact or IDU; (3) have a creatinine clearance of greater than 60 mL/min, and (4) have been screened and treated for other sexually transmitted infections (STI). Women of reproductive age requesting PrEP should also have a documented pregnancy test before initiating therapy. If a woman is pregnant or becomes pregnant while taking PrEP, providers should discuss the risks and benefits of continuing therapy. Providers are encouraged to anonymously submit outcome information to the ARV Use in Pregnancy Registry for women who choose to stay on PrEP while pregnant. Repeat HIV and STI testing should be done every 2 to 3 months in addition to renal function tests. No more than a 90-day supply of TDF/FTC should be provided at one time, although prescription renewals can be given if the above criteria remain fulfilled. As always, patients should be counseled on other mechanisms of risk reduction and adherence.

Long-term safety and outcomes of HIV-negative adults and following fetal exposure remain unknown. Any serious adverse events that occur as a result of taking TDF/FTC for PrEP should be reported to the FDA’s MedWatch (http://www.fda.safety/medwatch).

Postexposure Prophylaxis of HIV Infection

The scarcity of data describing occupationally acquired HIV infection makes it difficult to quantify the risk of transmission associated with exposure of health care workers to an HIV-infected source. Pooled data from multiple studies demonstrated HIV transmission in 20 health care workers out of more than 6000 workers who sustained a needlestick injury from an HIV-infected patient, yielding a transmission rate of 0.33%. HIV transmission due to mucosal exposure was even more uncommon (0.09%), and transmission from exposure of intact skin has not been described.

Despite poorly characterized risks and benefits, postexposure prophylaxis with ART is recommended for health care workers sustaining percutaneous, mucus membrane, or nonintact skin exposure to an HIV-infected source. HIV antibody testing of the worker should be done at the time of exposure and repeated at 6 weeks, 12 weeks, and 6 months after exposure. If given, prophylaxis should be administered as soon as possible, preferably within hours after the exposure. Recommended prophylactic regimens typically contain a two-drug combination of NRTIs; coformulations of zidovudine plus lamivudine (Combivir) and emtricitabine plus tenofovir (Truvada) are used extensively and have good tolerability. Three-drug HAART regimens including a PI are recommended for more severe exposures. The duration of postexposure prophylaxes is typically 4 weeks. The recommendations for prophylaxis have been expanded to include nonoccupational exposures such as unanticipated sexual or needle-sharing behavior.

References

1.     Adult Prevention and Treatment of Opportunistic Infections Guidelines Working Group. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents [draft]. 2008. Available at http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf ; [accessed July 9, 2015].

2.    Branson B. Current HIV epidemiology and revised recommendations for HIV testing in health care settings. J Med Virol. 2007;79(Suppl. 1):S6–10.

3.     Centers for Disease Control and Prevention. Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep 61:586–589, 2012.

4.    Centers for Disease Control and Prevention. Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep 60:65–68, 2011.

5.     Hirsch M.S. Initiating therapy: What to start, what to use. J Infect Dis. 2008;197(Suppl. 3):S252–S260.

6.      Joint United Nations Programme on HIV/AIDS. UNAIDS World AIDS Day Report. 2008. Available at: http://www/unaids.org/en/media/unaids/contentassets/docum [Accessed August 15, 2012].

7.    Landon B.E., Wilson I.B., McInnes K., et al. Physician specialization and the quality of care for human immunodeficiency virus infection. Arch Intern Med. 2005;165(10):1133–1139.

8.    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services; 2012. Available at: http://aidsinfo.nih.gov/Guidelines/HTML/1/adult-and-adolescent-treatment-guideline/0 (accessed August 15, 2012).

9.     Thompson MA, Aberg JA, Hoy J, et al. Antiretroviral treatment of adult HIV infection: 2012 Recommendations of the International AIDS Society-USA Panel. JAMA 2012; 308:387– 402.

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