1587CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

TABLE 202-21 Antiretroviral Drugs Most Commonly Used in the Treatment of HIV Infection

DRUG STATUS INDICATION DOSE IN COMBINATION SUPPORTING DATA TOXICITY

Nucleoside or Nucleotide Reverse Transcriptase Inhibitors

Zidovudine (AZT,

azidothymidine,

*

Retrovir, 3′azido3′-deoxythymidine)

Licensed Treatment of HIV infection

in combination with other

antiretroviral agents

200 mg q8h or 300 mg bid 19 vs 1 death in original placebo-controlled

trial in 281 patients with AIDS or ARC

Anemia,

granulocytopenia,

myopathy, lactic acidosis,

hepatomegaly with

steatosis, headache,

nausea, nail pigmentation,

lipid abnormalities,

lipoatrophy,

hyperglycemia

Prevention of maternalfetal HIV transmission

In pregnant women with CD4+ T-cell count

≥200/μL, AZT PO beginning at weeks 14–34

of gestation plus IV drug during labor and

delivery plus PO AZT to infant for 6 weeks

decreased transmission of HIV by 67.5% (from

25.5% to 8.3%); n = 363

Lamivudine (Epivir,

2′3′-dideoxy-3′-

thiacytidine, 3TC)

Licensed In combination with other

antiretroviral agents

for the treatment of HIV

infection

150 mg bid

300 mg qd

In combination with AZT superior to AZT

alone with respect to changes in CD4+ T-cell

counts in 495 patients who were zidovudinenaïve and 477 patients who were zidovudineexperienced; overall CD4+ T-cell counts for

the zidovudine group were at baseline by

24 weeks, while in the group treated with

zidovudine plus lamivudine, they were

10–50 cells/μL above baseline; 54% decrease

in progression to AIDS/death compared with

AZT alone

Flare of hepatitis in HBVco-infected patients who

discontinue drug

Emtricitabine (FTC,

Emtriva)

Licensed In combination with other

antiretroviral agents

for the treatment of HIV

infection

200 mg qd Comparable to lamivudine in combination with

stavudine and nevirapine/efavirenz

Hepatotoxicity in HBVco-infected patients who

discontinue drug, skin

discoloration

Abacavir (Ziagen) Licensed For treatment of HIV

infection in combination

with other antiretroviral

agents

300 mg bid Abacavir + AZT + 3TC equivalent to indinavir

+ AZT + 3TC with regard to viral load

suppression (~60% in each group with

<400 HIV RNA copies/mL plasma) and

CD4+ T-cell increase (~100/μL in each group)

at 24 weeks

Hypersensitivity reaction

In HLA-B5701+ individuals

(can be fatal); fever, rash,

nausea, vomiting, malaise

or fatigue, and loss of

appetite

Tenofovir disoproxil

fumarate (Viread)

Licensed For use in combination

with other antiretroviral

agents when treatment is

indicated

300 mg qd Reduction of ~0.6 log in HIV-1 RNA levels

when added to background regimen in

treatment-experienced patients

Renal, osteomalacia,

flare of hepatitis in HBVco-infected patients who

discontinue drug

Tenofovir alafenamide

(Vemlidy)

Licensed In combination with

emtricitabine and other

antiretroviral agents

for treatment of HIV-1

infection

25 mg qd 92% of patients treated in combination with

emtricitabine, elvitegravir, and cobicistat had

HIV-1 RNA levels <50 copies/mL

Nausea, less renal

toxicity than tenofovir

disoproxil fumarate

Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine (Viramune) Licensed In combination with other

antiretroviral agents for

treatment of progressive

HIV infection

200 mg/d × 14 days then

200 mg bid

or

400 mg extended release

qd

Increase in CD4+ T-cell count, decrease in

HIV RNA when used in combination with

nucleosides

Skin rash, hepatotoxicity

Efavirenz (Sustiva) Licensed For treatment of HIV

infection in combination

with other antiretroviral

agents

600 mg qhs Efavirenz + AZT + 3TC comparable to

indinavir + AZT + 3TC with regard to viral

load suppression (a higher percentage of

the efavirenz group achieved viral load

<50 copies/mL, but the discontinuation rate

in the indinavir group was unexpectedly high,

accounting for most treatment “failures”);

CD4 cell increase (~140/μL in each group) at

24 weeks

Rash, dysphoria, elevated

liver function tests,

drowsiness, abnormal

dreams, depression, lipid

abnormalities, potentially

teratogenic

Etravirine (Intelence) Licensed In combination with

other antiretroviral

agents in treatmentexperienced patients

whose HIV is resistant to

nonnucleoside reverse

transcriptase inhibitors

and other antiretroviral

medications

200 mg bid Higher rates of HIV RNA suppression

to <50 copies/mL (56% vs 39%); greater

increases in CD4+ T-cell count (89 vs

64 cells) compared to placebo when given in

combination with an optimized background

regimen

Rash, nausea,

hypersensitivity reactions

(Continued)

1588 PART 5 Infectious Diseases

TABLE 202-21 Antiretroviral Drugs Most Commonly Used in the Treatment of HIV Infection

DRUG STATUS INDICATION DOSE IN COMBINATION SUPPORTING DATA TOXICITY

Rilpivirine (Edurant) Licensed In combination with

other drugs in previously

untreated patients when

treatment is indicated.

25 mg qd Noninferior to efavirenz with respect to

suppression at week 48 in 1368 treatmentnaive individuals, except in patients with

pretherapy HIV RNA levels >100,000 where it

was inferior

Nausea, dizziness,

somnolence, vertigo, less

CNS toxicity and rash

than efavirenz

Protease Inhibitors

Ritonavir (Norvir) Licensed In combination with other

antiretroviral agents for

treatment of HIV infection

when treatment is

warranted

600 mg bid (also used

in lower doses as

pharmacokinetic booster)

Reduction in the cumulative incidence of

clinical progression or death from 34% to 17%

in patients with CD4+ T-cell count <100/μL

treated for a median of 6 months

Nausea, abdominal

pain, hyperglycemia,

fat redistribution, lipid

abnormalities, may alter

levels of many other

drugs, paresthesias,

hepatitis

Atazanavir (Reyataz) Licensed For treatment of HIV

infection in combination

with other antiretroviral

agents

400 mg qd or 300 mg qd +

ritonavir 100 mg qd when

given with efavirenz

Comparable to efavirenz when given in

combination with AZT + 3TC in a study of

810 treatment-naïve patients; comparable

to nelfinavir when given in combination with

stavudine + 3TC in a study of 467 treatmentnaïve patients

Hyperbilirubinemia, PR

prolongation, nausea,

vomiting, hyperglycemia,

fat maldistribution, rash

transaminase elevations,

renal stones

Darunavir (Prezista) Licensed In combination with

100 mg ritonavir for

combination therapy in

treatment-experienced

adults

600 mg + 100 mg ritonavir

twice daily with food

At 24 weeks, patients with prior extensive

exposure to antiretrovirals treated with a new

combination including darunavir showed a

–1.89-log change in HIV RNA levels and a

92-cell increase in CD4+ T cells compared

with –0.48 log and 17 cells in the control arm

Diarrhea, nausea,

headache, skin

rash, hepatotoxicity,

hyperlipidemia,

hyperglycemia

Entry Inhibitors

Enfuvirtide (Fuzeon) Licensed In combination with other

agents in treatmentexperienced patients

with evidence of HIV-1

replication despite

ongoing antiretroviral

therapy

90 mg SC bid In treatment of experienced patients, superior

to placebo when added to new optimized

background (37% vs 16% with <400 HIV RNA

copies/mL at 24 weeks; + 71 vs + 35 CD4+ T

cells at 24 weeks)

Local injection reactions,

hypersensitivity

reactions, increased rate

of bacterial pneumonia

Maraviroc (Selzentry) Licensed In combination with other

antiretroviral agents in

adults infected with only

CCR5-tropic HIV-1

150–600 mg bid depending

on concomitant

medications (see text)

At 24 weeks, among 635 patients with

CCR5-tropic virus and HIV-1 RNA >5000

copies/mL despite at least 6 months of prior

therapy with at least 1 agent from 3 of the

4 antiretroviral drug classes, 61% of patients

randomized to maraviroc achieved HIV RNA

levels <400 copies/mL compared with 28% of

patients randomized to placebo

Hepatotoxicity,

nasopharyngitis, fever,

cough, rash, abdominal

pain, dizziness,

musculoskeletal

symptoms

Ibalizumab (Trogarzo) Licensed In combination with other

antiretroviral agents in

patients with multidrugresistant HIV-1

Single loading dose of

2000 mg followed by a

maintenance dose of

800 mg every 2 weeks

At 25 weeks, 50% of patients with multidrug resistant HIV-1 with HIV-1 RNA

>1000 copies/mL treated with an optimized

background of 1 active drug and ibalizumab

achieved HIV RNA levels <200 copies/mL

Rash, diarrhea, nausea

Integrase Inhibitor

Raltegravir (Isentress) Licensed In combination with other

antiretroviral agents

400 mg bid At 24 weeks, among 436 patients with 3-class

drug resistance, 76% of patients randomized

to receive raltegravir achieved HIV RNA

levels <400 copies/mL compared with 41% of

patients randomized to receive placebo

Nausea, headache,

diarrhea, CPK elevation,

muscle weakness,

rhabdomyolysis

Elvitegravir

(Available only in

combination with

cobicistat, tenofovir,

and emtricitabine

[Stribild])

Licensed Fixed-dose combination 1 tablet daily Noninferior to raltegravir or atazanavir/

ritonavir in treatment-experienced patients.

Diarrhea, nausea, upper

respiratory infections,

headache

Dolutegravir (Tivicay) Licensed In combination with other

antiretroviral agents

50 mg daily for treatmentnaïve patients

50 mg twice daily for

treatment-experienced

patients or those also

receiving efavirenz or

rifampin

Noninferior to raltegravir, superior to efavirenz

or darunavir/ritonavir

Insomnia, headache,

hypersensitivity

reactions, hepatotoxicity

Bictegravir

(Available only in

combination with

tenofovir alafenamide

and emtricitabine

[Biktarvy])

Licensed For treatment of HIV

infection in adults

50 mg bictegravir/25 mg

tenofovir alafenamide/

200 mg emtricitabine qd

Noninferior to dolutegravir/tenofovir/

emtricitabine and non-inferior to dolutegravir/

abacavir/lamivudine

Nausea, diarrhea,

headache

(Continued)

(Continued)

1589CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

TABLE 202-21 Antiretroviral Drugs Most Commonly Used in the Treatment of HIV Infection

DRUG STATUS INDICATION DOSE IN COMBINATION SUPPORTING DATA TOXICITY

Cabotegravir

(Vocabria)

Licensed In combination with

rilpivirine for treatment of

HIV infection in adults

Oral lead-in of 30 mg +

25 mg rilpivirine for

1 month; followed by an

initial injection of 600 mg

(3 mL) IM + 900 mg (3 mL)

rilpivirine IM; followed

by monthly injections of

400 mg (2 mL) IM + 600 mg

(2 mL) rilpivirine IM

Noninferior to abacavir/dolutegravir/

lamivudine or dolutegravir + 2 nucleoside/tide

reverse transcriptase inhibitors

Noninferior to nonnucleoside reverse

transcriptase inhibitor + 2 nucleoside/

tide reverse transcriptase inhibitors or a

protease inhibitor + 2 nucleoside/tide reverse

transcriptase inhibitors or an integrase

inhibitor and 2 nucleoside/tide reverse

transcriptase inhibitors

Injection site reactions

*Initial trade names are provided. Generic forms may be available.

Abbreviations: ARC, AIDS-related complex; NRTIs, nonnucleoside reverse transcriptase inhibitors.

(Continued)

The HIV-1 protease inhibitors (saquinavir, indinavir, ritonavir,

nelfinavir, amprenavir, fosamprenavir, lopinavir/ritonavir, atazanavir, atazanavir/cobicistat, tipranavir, darunavir, and darunavir/

cobicistat) are an important part of the therapeutic armamentarium

of antiretrovirals. While possessing antiviral properties of its own,

ritonavir is typically used as a pharmacokinetic enhancer due to its

high affinity for several isoforms of cytochrome P450 (3A4, 2D6)

leading to large increases in the plasma concentrations of co-administered drugs metabolized by these pathways. As in the case of

reverse transcriptase inhibitors, resistance to protease inhibitors can

develop rapidly in the setting of monotherapy, and thus these agents

should be used only as part of combination therapeutic regimens.

Based on superior efficacy and side-effect profile, ritonavir-boosted

darunavir in combination with emtricitabine and tenofovir (disoproxil or alafenamide) is the protease inhibitor strategy preferred

for initial therapy in patients with CrCl >70 (tenofovir disoproxil)

or >30 (tenofovir alafenamide) according to the DHHS Panel on the

use of antiretroviral drugs.

Integrase strand transfer inhibitors act by blocking the action

of the HIV integrase enzyme and thus preventing integration of

the HIV provirus into the host cell genome. They are among the

most potent and safest of the antiretroviral drugs and frequently

part of initial combination regimens. The five licensed integrase

inhibitors are raltegravir, cabotegravir, elvitegravir, dolutegravir,

and bictegravir. Cabotegravir is an integrase inhibitor that is given

in combination with rilpivirine as a monthly injection. Prior to initiation of the monthly injections, patients should initially be treated

with oral preparations of the two drugs to be sure they are well tolerated. Elvitegravir is always given in combination with cobicistat,

which acts to boost the concentrations of elvitegravir. Cobicistat

also inhibits tubular secretion of creatinine, resulting in increases

in serum creatinine, and is not recommended for patients with

estimated creatinine clearances <70 mL/min. Dolutegravir has been

associated with a slight increase (0.2 vs 0.1%) in the incidence of

neural tube defects in infants exposed to dolutegravir at the time of

conception. Bictegravir is available only in combination with tenofovir alafenamide and emtricitabine. When used as part of initial

ART, integrase inhibitor–containing regimens have been associated

with greater weight gain than nonnucleoside reverse transcriptase

inhibitor– or protease inhibitor–containing regimens.

Entry inhibitors act by interfering with the binding of HIV to

its receptor or co-receptor or by interfering with the process of

fusion (see above). The first drug in this class to be licensed was the

fusion inhibitor enfuvirtide, or T-20, followed by the CCR5 antagonist maraviroc. The anti-CD4 monoclonal antibody ibalizumab

was licensed in 2018, and the small molecule fostemsavir in 2020.

Given that maraviroc is effective only against CCR5-tropic viruses,

a co-receptor tropism assay should be performed when use of this

agent is being considered.

PRINCIPLES OF THERAPY

The principles of therapy for HIV infection have been articulated by a panel sponsored by the U.S. Department of Health and

Human Services as a working group of the NIH Office of AIDS

Research Advisory Council. These principles are summarized in

Table 202-23. As noted in these guidelines, ART of HIV infection

does not lead to eradication or cure of HIV. The possible exceptions

are a limited number of individuals with HIV infection and cancer

who received allogeneic stem cell transplants from donors who

were homozygous for the CCR5Δ32 mutation (see above) and thus

resistant to HIV infection.

Treatment decisions must consider the fact that one is dealing

with a chronic infection that requires daily therapy. Patients initiating antiretroviral therapy must be willing to commit to life-long

treatment and understand the importance of adherence to their

prescribed regimen. The importance of adherence is illustrated

by the observation that treatment interruption is associated with

rapid increases in HIV RNA levels, rapid declines in CD4+ T-cell

counts, and an increased risk of clinical progression. While it seems

reasonable to assume that the complications associated with ART

could be minimized by intermittent treatment regimens designed

to minimize exposure to the drugs in question, all efforts to do

so have paradoxically been associated with an increase in serious

adverse events in the patients randomized to intermittent therapy,

demonstrating that some “non-AIDS-associated” serious adverse

events such as heart attack and stroke are linked to HIV replication.

Thus, unless contraindicated for reasons of toxicity, patients started

on ART should remain on ART.

At present, the U.S. Department of Health and Human Services

Guidelines panel recommends that everyone with HIV infection

be treated with ART and that therapy be initiated a soon as possible after diagnosis. Therapy has been associated with a decrease

in disease progression in patients at all stages of HIV infection

and leads to a decrease in the risk of transmission of infection. In

addition, one may wish to administer a 6-week course of therapy to

uninfected individuals immediately following a high-risk exposure

to HIV. The combination of tenofovir and emtricitabine is also

licensed for pre-exposure prophylaxis in individuals at high risk of

HIV infection, as is an injectable, long-acting formulation of cabotegravir that may be even more effective. For patients diagnosed

with an opportunistic infection and HIV infection at the same time

and a CD4+ count >50 cells/μL, one may consider a 2- to 4-week

delay in the initiation of antiretroviral therapy during which time

treatment is focused on the opportunistic infection. This delay may

decrease the severity of any subsequent immune reconstitution

inflammatory syndrome by lowering the antigenic burden of the

opportunistic infection. This is particularly true for patients with

TB or cryptococcal infections of the central nervous system. For

patients with advanced HIV infection (CD4+ <50 cells/μL), however, ART should be initiated as soon as possible.

Once the decision has been made to initiate therapy, the health

care provider must decide which drugs to use as the first regimen.

The decision regarding choice of drugs not only will affect the

immediate response to therapy but also will have implications

regarding options for future therapeutic regimens. The initial regimen is usually the most effective insofar as the virus has yet to

1590 PART 5 Infectious Diseases

O

O

O

HN

N

N3

CH3

H

HO

H

O

O P

O

HN O P

N

N

NH2 O

O

Tenofovir alafenamide

O 1/2

O

O

OPh

HO

OH

NH

CH3 H3C

NH2

Nucleoside or Nucleotide Reverse Transcriptase Inhibitors

Zidovudine

NH

HO–

HO

N

O

O O

O

O O

O O

O

N

N

O

O

N

N

NH2

N

N

Didanosine

O

O O

O

N

N

H CH3

NH2

HOCH2

N

N

Stavudine

Zalcitabine

O

H

H

OH

Lamivudine Tenofovir disoproxil fumarate

CH3

HO2C

CO2H

H

H

C C

CH2OH 2

H2N H2SO4

S

H2N

F

N

S

N

O

Emtricitabine

O

N

HN

N

N

Abacavir

N

N

N

N

N

OH

N

H

N N O

H

O Cl

Delavirdine

Nonnucleoside Reverse Transcriptase Inhibitors

N NH

CH–CH3

CH3 SO2

CH3

CH3

CH3 SO2 OH

H

C

O

N N

N

C

N

C N

N N N

N

N

O

N

H

Nevirapine

Rilpivirine

Efavirenz Etravirine

F3C

O

H

N N

N

NH2

N

Br

H3C CH3

HN NH

O

H

N

O

O

O O

O

O

O

O

OH

OH OH

O

O OH H3C

CH3

H3C CH3

O

H

H

H

Lopinavir

CH3

H CH3 3C

OH

O OH

HO

O

O

O

N

N

N

N

N

N

N

O O

OH H

N

N

H

O

H

H

O

NH NH

Protease Inhibitors

NHC(CH3)3

NHC(CH3)3

NH2

×CH3SO3H

SO2

CF3

H3C

CH3

NH2

• C2H5OH

• H2SO4

NH2

SO

O

OH

Saquinavir mesylate

H

N

H

N H

N N

H

N

H

S

S

S

N

N

H H N

S

H

Ritonavir

Tipranavir Darunavir

O O

O O

H3CO

OCH3 • H2S H

N N

H

OH

Atazanavir

Nelfinavir mesylate

Indinavir sulfate

N

Amprenavir

NHtBu

HN O O

HN

H

N N

H N

O

H

N N

H

N

N

O

OH O

O O

FIGURE 202-46 Molecular structures of antiretroviral agents.

be under any selective pressure to develop significant drug resistance. HIV is capable of rapidly developing resistance to any single

agent, and therapy must be given as a multidrug combination.

Given that patients can be infected with viruses that harbor drug

resistance mutations, it is recommended that a viral genotype be

done prior to the initiation of therapy to optimize the selection of

antiretroviral agents. The combination regimens currently recommended for initial therapy in most treatment-naïve patients are listed

in Table  202-24. It is currently debated whether treatment-naïve

individuals with <50 copies/mL of HIV RNA benefit from ART.

While these individuals are at low risk of disease progression in the

short term, they do have evidence of persistent immune activation

1591CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

that may have long-term consequences. Following the initiation of

therapy, one should expect a rapid, at  least 1-log (tenfold) reduction in plasma HIV RNA levels within 1–2  months and then a

slower decline in plasma HIV RNA levels to <50 copies/mL within

6 months. During this same time there should be a rise in the CD4+

T-cell count of 100–150/cells μL that is also particularly brisk during the first month of therapy. Subsequently, one should anticipate

a CD4+ T-cell count increase of 50–100 cells/year until numbers

approach normal. Many clinicians feel that failure to achieve these

endpoints is an indication for a change in therapy. Other reasons

for a change in therapy include a persistently declining CD4+ T-cell

count, a consistent increase in HIV RNA levels to >200 copies/mL,

clinical deterioration, or drug toxicity (Table 202-25). As in the case

of initiating therapy, changing therapy may have a lasting impact

on future therapeutic options. When changing therapy because

of treatment failure (clinical progression or worsening laboratory

parameters), it is important to attempt to provide a regimen with

at least two new active drugs. This decision can be guided by resistance testing (see below). In the patient in whom a change is made

for reasons of drug toxicity, a simple replacement of one drug is

reasonable. It should be stressed that in attempting to sort out a

drug toxicity it may be advisable to hold all therapy for a period of

time to distinguish between drug toxicity and disease progression.

Drug toxicity will usually begin to show signs of reversal within

1–2 weeks. Prior to changing a treatment regimen because of drug

failure, it is important to ensure that the patient has been adherent

to the prescribed regimen. As in the case of initial therapy, the simpler the new therapeutic regimen, the easier it is for the patient to

Entry Inhibitors

O

O

O

O

O

O

O

O

O

H

N N

H

H2N

H2N

H2N

NH2

H2N HO

HO

NH2

Enfuvirtide

Maraviroc

O

O

O

O OH

OH

OH

H

N N

H

NH2

NH

NH

HN

O

O

H

N N

H O

O

O

HO

H

N N

H

O

O

H

N N

H

N NH

O

O

HO

HO

HO

H

N N

H

O

O

O

H

N N

H

N

H

O

O

O

O O

O

F

H

N N

N

O

F

H2N

NH2

NH2

O O

HN

N

H

N

H

H

N H

N

O

NH

HO O

HN

O

O

OHO

N

H

H

N

O

O

N

H

H

N

O

H

N

O

N

H

N

H

O

O

OH O

OH

N

H

H

N

O

O

O

O

O

NH

NH

N

H

HN

HN

N

N Me

MeMe

Ibalizumab

N

Me

N

H

H

N

H

N

H

N O

O

F

O

O O

FO

F F

F

N

O OH

H

Integrase Inhibitors

N

O

O

O OH

H

N N N

O

O F

Cl

F

Elvitegravir Raltegravir

Dolutegravir

Bictegravir

N

HO

OH

N

O

N

N

H

O

ONa O

O

H

Me

Cabotegravir

F F

N 11a

3

O

N

FIGURE 202-46 (Continued)

1592 PART 5 Infectious Diseases

TABLE 202-22 Combination Formulations of Antiretroviral Drugs

NAME COMBINATION

Atripla* Tenofovir disoproxil fumarate + emtricitabine + efavirenz

Biktarvy* Tenofovir alafenamide + emtricitabine + bictegravir

Cabenuva* Cabotegravir + rilpivirine (long-acting injection)

Cimduo Tenofovir disoproxil fumarate + lamivudine

Combivir Zidovudine + lamivudine

Complera* Tenofovir disoproxil fumarate+ emtricitabine + rilpivirine

Delstrigo* Doravirine +tenofovir disoproxil fumarate + lamivudine

Descovy Tenofovir alafenamide + emtricitabine

Dovato* Dolutegravir + lamivudine

Dutrebis Raltegravir + lamivudine

Epzicom Abacavir + lamivudine

Evotaz Atazanavir + cobicistat

Genvoya* Tenofovir alafenamide + emtricitabine + elvitegravir + cobicistat

Juluca* Dolutegravir + rilpivirine

Kaletra Lopinavir + ritonavir

Odefsey* Tenofovir alafenamide + emtricitabine + rilpivirine

Prezcobix Darunavir + cobicistat

Stribild* Tenofovir disoproxil fumarate + emtricitabine + elvitegravir + cobicistat

Symfi* Tenofovir disoproxil fumarate + lamivudine + efavirenz (600 mg)

Symfi Lo* Tenofovir disoproxil fumarate + lamivudine + efavirenz (400 mg)

Symtuza* Darunavir + tenofovir alafenamid + emtricitabine +cobicistat

Temixys Tenofovir disoproxil fumarate + lamivudine

Triumeq* Abacavir + lamivudine + dolutegravir

Truvada Tenofovir disoproxil fumarate + emtricitabine

Trizivir Zidovudine + lamivudine + abacavir

*

Complete, once-daily, single-tablet regimens.

FIGURE 202-47 Amino acid substitutions conferring resistance to antiretroviral drugs. For each amino acid residue, the letter above the bar indicates the amino acid

associated with wild-type virus and the letter(s) below indicate the substitution(s) that confer viral resistance. The number shows the position of the mutation in the

protein. Mutations selected by protease inhibitors in Gag cleavage sites are not listed. HR1, first heptad repeat; NAMs, nRTI-associated mutations; nRTI, nucleoside

reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Amino acid abbreviations: A, alanine; C, cysteine; D, aspartate;

E, glutamic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine;

T, threonine; V, valine; W, tryptophan; Y, tyrosine. (Reprinted with permission from the International Antiviral Society—USA. AM Wensing et al: 2019 resistance mutations

update. Top Antivir Med 27:111, 2019. Updated information [and thorough explanatory notes] available at www.iasusa.org.)

TABLE 202-23 Principles of Therapy of HIV Infection

1. Ongoing HIV replication leads to immune system damage, progression to

AIDS, and systemic immune activation.

2. Plasma HIV RNA levels indicate the magnitude of HIV replication and the rate

of CD4+ T-cell destruction. CD4+ T-cell counts indicate the current level of

competence of the immune system.

3. Maximal suppression of viral replication is a goal of therapy; the greater the

suppression the less likely the appearance of drug-resistant quasispecies.

4. The most effective therapeutic strategies involve the simultaneous initiation

of combinations of effective anti-HIV drugs with which the patient has not

been previously treated and that are not cross-resistant with antiretroviral

agents that the patient has already received.

5. The antiretroviral drugs used in combination regimens should be used

according to optimum schedules and dosages.

6. The number of available drugs is limited. Any decisions on antiretroviral

therapy have a long-term impact on future options for the patient.

7. Women should receive optimal antiretroviral therapy regardless of pregnancy

status.

8. The same principles apply to children and adults. The treatment of HIVinfected children involves unique pharmacologic, virologic, and immunologic

considerations.

9. Compliance is an important part of ensuring maximal effect from a given

regimen. The simpler the regimen, the easier it is for the patient to be

compliant.

Source: Modified from Principles of Therapy of HIV Infection, USPHS, and the Henry

J. Kaiser Family Foundation.

1593CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

FIGURE 202-47 (Continued)