Vww

New virrfln panicle

Wraf Mflfuïafi'pn fliiii

Protease [ftfitätofs

Aiazanair

Revr irul

Darunavir

FôSamprÊrtavir

Irnjinfluir

Lop niLvir.Tiluravir Nö linavir Ritonavir Saquinavir Tipranavir integration. Transcription anc Translation Inhibitors: imegrase Inliibiiwa (raUegravir)

FIGURE 87-1. Life cycle of HIV and targets for antiretroviral drugs. (From Fletcher CV, Kakuda TN. Human immunodeficiency virus infection. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 2258, with permission.)

After the virus has attached to CD4 and chemokine receptors, another viral glycoprotein (gp41) assists with viral fusion to the cell and internalization of the viral contents. The viral contents include single-stranded RNA, an RNA-dependent DNA polymerase (also known as reverse transcriptase), and other enzymes. Using the single-stranded viral RNA as a template, reverse transcriptase synthesizes a complementary strand of DNA. The single-stranded viral RNA is removed from the newly formed DNA strand by ribonuclease H, and reverse transcriptase completes the synthesis of double-stranded DNA. The viral reverse transcriptase enzyme is highly error-prone, and many mutations occur in the conversion of RNA to DNA. This inefficient reverse transcription activity is responsible for HIV's ability to rapidly mutate and develop drug resistance.

A chronic infection is established when the double-stranded DNA migrates to the host cell nucleus and is integrated into the host cell chromosome by an HIV enzyme called integrase. Once the cell becomes activated by antigens or cytokines, HIV replication starts: host DNA polymerase transcribes viral DNA into messenger RNA, and messenger RNA is translated into viral proteins. These proteins assemble beneath the bilayer of the host cell, a nucleocapsid forms containing these proteins, and the virus buds from the cell. After budding, the virus matures when an HIV protease enzyme cleaves large polypeptides into smaller functional proteins. Without this process, the virus is unable to infect other cells.

During the early stages of infection, approximately 10 billion virions can be produced each day. Most of the cells containing these viruses will be lysed as a result of budding virions, killed by cytotoxic T-lymphocytes, or undergo apoptosis. However, virus will be protected within some cells (macrophages, T cells in lymph nodes), which can stay dormant for years. The initial immune response against HIV is relatively effective, but it is unable to completely clear the infection, and the patient enters a latent, asymptomatic or mildly symptomatic stage lasting 5 to 15 years. During this time, a high rate of viral replication can be seen in the lymph nodes. Eventually immune deficiency occurs when the body is no longer able to replenish helper T cells at a rate equal to that at which HIV is destroying them.

O The goal of therapy is to maximally and durably suppress HIV replication in order to restore and preserve immune system function and minimize morbidity and mortality. Because HIV replication has been found in all areas of the body, it is important to use potent drug therapy that can achieve adequate concentrations in all tissues, including protected sites such as the brain and genital tract.

clinical presentation and diagnosis

HIV diagnosis is made either by a positive HIV enzyme-linked immunosorbent assay (ELISA) or rapid test (these tests may be positive as soon as 3-6 weeks after in fection) and then confirmed by a positive confirmatory test, usually the HIV Western blot (WB) (Table 87-1).

Patients who are acutely infected with HIV may be asymptomatic or present with signs and symptoms associated with any viral infection, such as fever, myalgias, lymphadenopathy, pharyngitis, or rash. Taken together, these are the "acute retroviral syndrome." Providers should consider the possibility of HIV infection in any patients with these findings and inquire about recent high-risk sexual encounters or other modes of exposure. Risk factors for HIV/AIDS infection include: men who have sex with men (MSM); history of or current IV drug use (needle or equipment sharing); unprotected sexual intercourse with high-risk individuals; the presence of other sexually transmitted infections (e.g., Chlamydia trachomatis or Neisseria gonorrhoeae); persons with coagulation/hemophilia disorders; and previous blood product recipients. Up to 50% of HIV-infected individuals are not aware of their status, thus identifying acutely infected patients and providing referral into HIV care is critical for preventing HIV transmission.2 In acute infection, HIV RNA concentrations in blood and the

genital tract are very high, increasing the risk of transmission to others. Increased infectiousness coupled with undiagnosed HIV infection in these patients may account for a substantial proportion of sexual HIV transmission.

If patients are not identified during acute infection, they may later present with various nonspecific symptoms such as myalgias, fatigue, weight loss, thrush, or symptoms associated with opportunistic infections. The U.S. Centers for Disease Control (CDC) currently recommends that patients aged 13 to 64 years in all health care settings undergo opt-out HIV testing, meaning that a separate consent form for testing is not needed after the patient has been informed that testing will be performed. For those patients in the high-risk groups mentioned above, HIV testing should be performed on an annual basis.4

The diagnosis of HIV infection is made either by a baseline serologic screening test such as the ELISA or a rapid test. If reactive, then a confirmatory test is performed. The WB is the gold standard confirmatory test and is commonly used. The WB is considered reactive if two of the three major bands (p24, gp41, and/or gp120/160) change color. The test is nonreactive if no viral bands are visible. If the test is indeterminate (one band visible), patients are retested in 2 to 3 months. This is most likely if a recent (i.e., less than 3-6 weeks) infection has occurred, and HIV antibodies have not yet been fully formed. In this case, a plasma HIV RNA concentration (reverse transcriptase polymerase chain reaction [RT-PCR]) should be evaluated. Patients with acute infection will generally have HIV RNA concentrations greater than 106 copies/

mL. HIV severity is determined by following: (a) the CD4+ lymphocyte count (CD4 count) and percentage and (b) HIV RNA (viral load). The CD4 percentage is followed because the absolute count may fluctuate and does not necessarily indicate a change in the patient's condition.

Table 87-1 HIV Diagnostic Tests

Minimum Time to

Test

Detection AFler Exposure

Sjimplelil Tested

Comments

Initial SifMning Trtlt

ELBA

J-Gwcefs

Plasma

11 nornetittiwi no furthci telling is n.ijj"c.tl uiitMi jiuic inficctkjrt jufvcted

HIV RNA nSMf

up T& 14 days

PUSillS

Otiiin if i«em ri^h-iisii eipos^e; if Initially negative r^fwiTit monilv; 1,5, and 6

fctfh'ififlri ¡fMtetxfy fiM-tipptcrfed

Detects f IIV anl i|jodi?s within minu les of san-ple arokaiion

[JiaiJiiK-* AJJVANil-

tjliHKr. plasma, o exal fluid

fieiiih HTV-1 and HH/-J

Kevwl Hjpm Hiv-I

plwnna c sejum

Detects

Antibody Test

Unl-tiofca Kivonitaiieii HIV l«r

watte

Whtlo (Hcioit plasma, qi serum

Detects rftf-1

Conlinwiory Trsti

Western Hot |W0J

J-t^eks

Plasma

Gold standard confirmatory lest

Ind rrtl ¡IHdtKiriOtllK«eiCi?(Ke

i-6 wKH

PI»™

iinvie to perform, ftoi requires expertise

assay flFA)

to intiifm?t fesutts

ELlS^enryme-linked immunosabent assay.

ELlS^enryme-linked immunosabent assay.

Clinical Presentation and Diagnosis of HIV

Patients with acute HIV infection may display symptoms described as "acute retroviral syndrome." Patients with chronic HIV infection may present with these same nonspecific symptoms and/or opportunistic infections.

Acute Retroviral Syndrome

The majority of patients may present with fever, lymphadenopathy, pharyngitis, and/ or rash. Other symptoms include:

• Myalgia or arthralgia

• Nausea and vomiting

• Hepatosplenomegaly

• Neurologic symptoms (meningoencephalitis, aseptic meningitis, peripheral neuropathy, facial palsy, or cognitive impairment or psychosis)

Opportunistic Infections

Depending on the severity of immunosuppression (the CD4+ T lymphocyte count), patients may present with the following opportunistic infections (grouped by CD4+ count):

Any CD4+ count

• Mycobacterium tuberculosis disease

• Bacterial pneumonia (commonly Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus)

• Herpes simplex virus disease

• Varicella zoster virus disease

• Bacterial enteric disease (most commonly Salmonella, Campylobacter, and Shigella)

• Bartonellosis

Less than 250 cells/mm

• Coccidioidomycosis

• Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)

• Oropharyngeal and esophageal candidiasis

• Kaposi's sarcoma or human herpesvirus-8 disease Less than 150 cells/mm

• Disseminated histoplasmosis Less than 100 cells/mm

• Cryptosporidiosis

• Microsporidiosis

Less than 50 cells/mm

• Disseminated Mycobacterium avium complex disease

• Cytomegalovirus disease

• Cryptococcosis, aspergillosis, and Toxoplasma gondii encephalitis Patient Encounter, Part 1

A 46-year-old Caucasian man with a history of hypertension and gastroesophageal reflux disease (GERD) comes to your clinic complaining of increased fatigue, shortness of breath, and cough. He has noticed feeling tired more easily for the past 3 months, but the difficulty breathing and cough appeared 2 weeks ago. After questioning him further, he says he has sex with men, but he has had the same sexual partner for the past 8 years. They do not use condoms. He also says that he smokes about one pack of cigarettes per day.

What information is suggestive of HIV/AIDS? What risk factors are present for having HIV/AIDS?

What additional information do you need to know before creating a treatment plan for this patient?

treatment

O The goals of treatment are to maximally and durably suppress viral replication, avoid the development of drug resistance, restore and preserve immune function, prevent opportunistic infections, and minimize drug adverse effects. Elimination of HIV is not possible with currently available therapies. Instead, maximal suppression of viral replication (defined as HIV RNA concentrations undetectable by the most sensitive assay available) is desired. After the initiation of antiretroviral therapy, a rapid decline to undetectable HIV RNA in 16 to 24 weeks is a predictor of improved clinical out-comes.5

'©' Degree of immune function preservation also correlates with decreased viral replication, and is measured by CD4+ T-cell counts. CD4 measures are the best predictor of progression to AIDS, and help decide when to initiate treatment. At CD4+ T-cell counts of 200 cells/mm and lower, patients require drug prophylaxis for op portunistic infections. Table 87-2 details the monitoring end points of HIV treatment for HIV RNA and CD4+ T-cell counts.

Six classes of drugs are available to treat HIV infection: nucleoside (NRTI)/nuc-leotide (NtRTI) reverse tran-scriptase inhibitor, protease inhibitor (PI), nonnuc-leoside reverse transcriptase inhibitor (NNRTI), fusion inhibitors, CCR5 inhibitors, and integrase inhibitors. Currently, combination antiretroviral drug therapy with three or more active drugs is the standard of care, which increases the durability of viral suppression and decreases the potential for the development of resistance. Two nucleoside (nucleotide) reverse transcriptase inhibitors and either a NNRTI or a ritonavir-boosted PI are the mainstay regimens of combination therapy in initial treatment. In the late 1980s, when only zidovudine was available, achieving and maintaining viral suppression for more than 4 months was rarely possible. As more agents became available in the mid-1990s (most notably the PIs), HIV RNA was suppressed to undetectable concentrations and maintained there for long periods of time. Currently recommended combination regimens decrease HIV RNA to less than 50 copies/mL in 80% to 90% of patients in clinical trials. Therefore, monotherapy with any agent or the use of NRTIs without a PI or NNRTI are not routine treatment options. Fusion inhibitors, CCR5 inhibitors, and integrase inhibitors are only FDA-approved for use in treatment experienced patients with drug resistance to NRTIs, NNRTIs, and/or PIs, although clinical trials are ongoing to determine their role in the initial treatment of HIV infection. Figure 87-1 details the mechanisms of action of the drug classes within the life cycle of HIV.

Table 87-2 Monitoring End Points for CD4+ T-Cell Counts and HIV RNA

CD4 - T Cell Counts HIV ANA Concentration

When to

Whento

Monitor?

Why?

Monitor?

Why?

{jDJll

Initial diagnosis

Assess need for ART

Start lherapy in

Inlllal diagnosis/

Establish baseline and

Stan ART m appropriate

IppffipllK

evihjolkrt

IW«d lor ART

pilk'nti

patients

Assess need ¡or 0c

Start Iherapy when

2-9 weets a'ter

iarly assessment of

DeciejseoFat least a

.ihC'iTOpiiiphytiilri

c-ourus less than

string or

legnren efficacy

1 log! copaeVrnL

it» ceHs/rrni'

chang ng ART

E^hry

Rr^'i Tyirtcj AH I:

jVnujigr' irirv.i'. ■

J 4monthiaiWr

A^s™ viiokjqic (iirkaCy

UndmciUljk" ItveH

room its

momlcr success of

of 100-ISflcefc/

starling ART

of regimen

Ireatrnervt

mrriVyefli

Noi leceiving ART:

Stan ART In

Ewry i-4 nrunlhs

Receiving AM assess

Slo.icHy ctecreaing levels

aura neod to

awiupriate

durability of viiologk

andta consislonlly low

IXVJin (her^

(Wlieflti

injfflytSSion with

Iwts

curreiil legmen

need for t*

Stwi tHerapy when

Not leceiving AffT;

^tart iheupiy in

chemoiyorihylaxii

counts les-s ih.an

monitor changes :n

a pf* opiate patents

200tellJAfW

virjl kji«J

AftT, amii enteral therapy: (X gpiwiuntlK inj^djon, Aiispn-d liorri Ret i.

AftT, amii enteral therapy: (X gpiwiuntlK inj^djon, Aiispn-d liorri Ret i.

Nonpharmacologic Interventions

® Patient adherence is a key component in treatment success. Drug therapy is required for a lifetime, as the virus begins to replicate at high levels when medications are stopped. Early HIV combination therapy was exceedingly complicated for patients, with multiple daily doses, varying food restrictions, and large pill burdens. Advances in delivery and formulation s now make possible once - or twice-daily dosing with fewer than six pills per day. Currently, a combination tablet of tenofovir + emtricitabine + efavirenz (Atripla) supplies a one pill, once-daily regimen. The use of low-dose ritonavir to enhance the concentrations of other PIs (known as pharmacokinetic enhancement or "boosting") allows for significantly fewer doses and lower pill burdens. Atazanavir with ritonavir boosting is a potent, once-daily PI option. These advances, however, do not replace the need for patient counseling by a trained pharmacist and a multidisciplinary approach to promoting adherence.

Counsel all patients initially and repeatedly on ways to prevent viral transmission. Preventing the spread of resistant virus is particularly important. Patients receiving antiretroviral therapy can still transmit virus to sexual partners, and to those with whom they share needles or other drug equipment. Where both partners are HlV-pos-itive, safe sex and needle practices reduce the risk of superinfection with differing strains of HIV and the transmission of other sexually transmitted diseases. General guidelines for preventing viral transmission include using condoms with a water-based lubricant for vaginal or anal intercourse, using condoms without lubricant or dental dams for oral sex, and not sharing equipment used to prepare, inject, or inhale drugs. Treating other sexually transmitted infections (STIs), particularly genital herpes, in HIV-infected patients may help to prevent HIV transmission. The presence of STIs increases genital tract HIV viral load, and correspondingly the risk of HIV transmission to sexual partners.

Nutrition and dietary counseling should also be included in the care of the HIV patient, as poor nutrition leads to poorer outcomes and complicates treatment. Antiretroviral therapy itself introduces a host of nutritional issues, including drug-food interactions, GI adverse effects that may affect appetite and limit dietary intake, lipid abnormalities, and fat redistribution. The American Dietetics Association currently recommends assessing HIV-infected patients for their level of nutritional risk and involving a registered dietician as part of the clinical team for optimal nutrition care.6

Pharmacologic Therapy for Antiretroviral-Na'ive Patients

Two major panels of experts publish guidelines for the treatment of HIV-infected individuals. Although the recommendations are quite similar, slight differences do exist between the Department of Health and Human Services (DHHS) Guidelines5 and the International AIDS Society-USA (IAS-USA) Panel Recommendations.7 The DHHS Guidelines are updated every 6 months and current and archived versions are available online at www.aidsinfo.nih.gov. The IAS-USA Guidelines were last updated in 2008, and in 2006 prior to that revision. Due to the intense research and constant modifications to therapeutic approaches in the treatment of HIV, the majority of the treatment algorithms and recommendations presented herein follow the most up-to-date information found in the DHHS recommendations.

'0' The decision of when to begin antiretroviral therapy is complex. Recommendations are based on the CD4+ T-cell count, which predicts disease-free survival (Table 87-3). Other factors to consider include the patient's viral load, willingness to begin therapy and maintain medication adherence, and the risk versus benefit of treating an asymptomatic patient. The clinical evidence is strongest for beginning treatment at CD4+ counts less than 200 cells/mm3, but more recent evidence from long-term studies and the availability of potent drugs with improved tolerability support earlier treatment at higher CD4+ counts. Once the decision is made to initiate treatment, the regimen is selected based on patient-specific factors. All recommended regimens for initial treatment contain either an NNRTI or a ritonavir-boosted PI in combination with two NRTIs (or NtRTI). The preferred agents are:

Table 87-3 Summary of Recommendations for Initiating Antiretroviral Therapy

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