Human Immunodeficiency Virus Disease: AIDS and Related Disorders¶

Chapter 208 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 208

Key Clinical Points¶

HIV-1 is the primary cause of global AIDS; HIV-2 is largely restricted to West Africa.
CDC staging (A, B, C) and CD4 categories (1, 2, 3) define clinical progression and immune status.
U=U: Undetectable viral load (<20 copies/mL) equals untransmittable sexually.
HIV-1 replication involves binding, fusion, reverse transcription, integration, assembly, and budding.
AIDS-defining illnesses include PCP, Kaposi's sarcoma (KS), Cryptococcosis, and various malignancies.
ART is the cornerstone of treatment, utilizing NRTIs, NNRTIs, PIs, and INSTIs.
Early ART initiation prevents progression to AIDS and reduces mortality.
Opportunistic infections like Toxoplasmosis and MAC are linked to specific CD4+ thresholds.
Genetic factors (e.g., HLA-B*57:01) influence disease progression and drug hypersensitivity.
Prevention includes PrEP, PEP, and various public health measures like needle exchange.

DEFINITION & CLASSIFICATION¶

• Overview: AIDS is a spectrum of immune deficiency caused by HIV. • Clinical Context: Initially identified in 1981; characterized by opportunistic infections and malignancies. • CDC Staging: → Stage A: Asymptomatic → Stage B: Symptomatic but not AIDS-defining → Stage C: AIDS-defining illness or CD4 <200 cells/µL • CD4 Categories (Table 1): → Category 1: ≥500 cells/µL → Category 2: 200–499 cells/µL → Category 3: <200 cells/µL • Clinical Perspective: View HIV as a continuum rather than just the strict definition of AIDS.

1.1 Etiologic Agent¶

• Classification: Retroviridae family, lentivirus subfamily. • HIV-1: Primary cause of global pandemic; multiple subtypes (M, N, O, P). → Subtype C: Dominates globally (~50%). → Subtype B: Prevalent in U.S., Europe, and Australia. • HIV-2: Confined mostly to West Africa. • Recombinants: CRF01_AE (Asia), CRF02_AG (Africa).

ETIOLOGY & PATHOPHYSIOLOGY¶

• Mechanism of Action: HIV causes immunodeficiency via CD4+ T cell depletion and chronic immune activation. • Viral Dynamics: → Replication Cycle: Binding (CD4/CCR5/CXCR4) → Fusion → Reverse Transcription → Integration → Assembly/Budding. → Key Enzymes: Reverse Transcriptase (RNA to DNA), Integrase (integration into host genome), Protease (cleavage of gag-pol precursor for maturation). • Genetic Factors (Table 6): → HLA-B57:01: Slower progression; risk of abacavir hypersensitivity. → CCR5 mutations: e.g., Δ32 leads to truncated protein and reduced R5 strain activity. → TLR/Immune Activation: Leads to accelerated aging, bone fragility, and cardiovascular disease (Table 4). • Viral Persistence:* → Latent Reservoir: Non-replicating cells harboring integrated DNA; not cleared by ART. → Evolution: Rapid diversification via mutation and recombination leads to 'quasispecies' and drug resistance.

3.1 Molecular Heterogeneity¶

• Variation: High in envelope proteins (gp120/gp41) due to immune selection; lower in reverse transcriptase.

CLINICAL FEATURES¶

• Acute HIV Syndrome: Fever, lymphadenopathy, rash, weight loss (2–4 weeks post-exposure). • Chronic Phase: May be asymptomatic for years. • AIDS-Defining Illnesses (Table 2): → Infections: PCP, Cryptococcosis, Toxoplasmosis, MAC, CMV retinitis. → Malignancies: Kaposi's sarcoma (KS), Lymphoma. → Other: Wasting syndrome, CNS infections. • Neurological Manifestations: → AIDS Dementia Complex (HAND). → PML, CNS Toxoplasmosis, CNS Lymphoma. • Physical Findings: → Lipodystrophy (fat redistribution). → Oral lesions (Candidiasis, Hairy Leukoplakia, KS).

DIFFERENTIAL DIAGNOSIS¶

• PCP: Differentiate from bacterial pneumonia and TB. • KS: Distinguish from other vascular tumors. • Cryptococcal Meningitis: Differentiate from Tuberculous meningitis (MRI shows basal meningeal enhancement). • Toxoplasmosis: Distinguish from CNS lymphoma in patients with CD4 <100.

Reference Tables¶

TABLE 208-2¶

Harrison's 22e, p.1557

	AGE ON DATE OF CD4 T+ LYMPHOCYTE TEST
	<1 YEAR		1–5 YEARS		6 YEARS THROUGH ADULT
STAGEa	CELLS/lL	%	CELLS/lL	%	CELLS/lL	%
1	≥1500	≥34	≥1000	≥30	≥500	≥26
	750–1499	26–33	500–999	22–29	200–499
3	<750	<26	<500	<22	<200	<14

TABLE 208-1 CDC Stage 3 (AIDS)-Defining Opportunistic Illnesses in HIV Infection Bacterial infections, multiple or…¶

Harrison's 22e, p.1557

Bacterial infections, multiple or recurrenta
Candidiasis of bronchi, trachea, or lungs
Candidiasis of esophagus
Cervical cancer, invasiveb
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy attributed to HIV
Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis,
or esophagitis (onset at age >1 month)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month’s duration)
Kaposi’s sarcoma
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or
extrapulmonary
Mycobacterium tuberculosis of any site, pulmonary,b disseminated, or
extrapulmonary
Mycobacterium, other species or unidentified species, disseminated or
extrapulmonary
Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia
Pneumonia, recurrentb
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age >1 month
Wasting syndrome attributed to HIV

TABLE 208-3 Estimated Per-Act Probability of Acquiring HIV from an Infected Source, By Exposure Act¶

Harrison's 22e, p.1562

TYPE OF EXPOSURE	RISK PER 10,000 EXPOSURES
Parenteral
Blood transfusion	9250
Needle-sharing during injection drug use	63
Percutaneous (needle-stick)	23

TABLE 208-4 Conditions Associated with Persistent Immune Activation and Inflammation in Patients with HIV Infection…¶

Harrison's 22e, p.1575

Accelerated aging syndrome
Bone fragility
Cancers
Cardiovascular disease
Diabetes
Kidney disease
Liver disease
Neurocognitive dysfunction

TABLE 208-5 Proposed Mechanisms of CD4+ T Cell Dysfunction and Depletion¶

Harrison's 22e, p.1577

DIRECT MECHANISMS	INDIRECT MECHANISMS
Loss of plasma membrane integrity due to viral budding	Aberrant intracellular signaling events
Interference with cellular RNA processing	Innocent bystander killing of viral antigen–coated cells
Syncytia formation	Inhibition of lymphopoiesis from reduced survival cytokines and lymphoid tissue integrity
	Activation-induced cell death
	Elimination of HIV-infected cells by virus- specific immune responses

TABLE 208-6 Host Genetic Factors Influencing HIV/AIDS Pathogenesis and Therapy Responses GENE a Genes in MHC Locus HLA-B¶

Harrison's 22e, p.1581

GENEa	GENETIC VARIATION	MECHANISMSb	GENETIC ASSOCIATIONSc
Genes in MHC Locus
HLA-B	B27 and B57	Altered presentation of specific HIV antigens	Slower progression to AIDS; lower viral load
	B*35	Restriction of specific HIV peptide presentation	Faster progression to AIDS; higher viral load
	HLA-Bw4	Providing ligands for activating KIR	Slower progression to AIDS
	B*57:01	Altered presentation of specific HIV antigens (as above); possible abacavir-specific activation of cytokine-producing CD8+ T cells in carriers of this allele	Slower progression to AIDS; higher risk of abacavir-associated hypersensitivity
	HLA-B? 21M allele	Enhanced HLA-E expression levels correlated with higher HLA-A expression and inhibition of NKG2A- expressing cells	Higher viral load, reduced CD4+ counts, and accelerated disease progression
	B*57:03 bearing the rs2523608-A allele	Altered presentation of specific HIV antigens	Variant overexpressed in HIV-1 controllers of African descent
HLA class I allele	Homozygosity of HLA-class I alleles	Reduced repertoire for epitope recognition	Faster progression to AIDS; increased risk of mother-to-child transmission
	Shared donor–recipient HLA alleles	Preadaptation of HIV strains	Faster progression to AIDS
	Rare HLA alleles	Limited adaptation of HIV strains; less frequent escape mutants	Protection against HIV infection
HLA class II allele	HLA-DRB1 alleles	Influence on protein specificity of CD4+ T cell responses to HIV Gag and Nef proteins	HLA-DRB115:02—lower viral load HLA-DRB103:01—higher viral load
HLA extended haplotype	A1-B8-DR3-DQ2 (AH 8.1)	Increased proinflammatory responses; higher TNF-α production	Faster progression to AIDS
HLA-C	rs9264942-C allele (35 kb upstream of HLA-C) in linkage with rs67384697-Del	Increased expression of HLA-C by reducing binding of miRNA-148a	Decreased viral load set point
	rs5010528-G (1 kb upstream of HLA-C)	Unknown	Higher risk of developing nevirapine-associated hypersensitivity
HCP5	rs2395029-G	Linkage disequilibrium with HLA-B*57:01	Lower viral load and slower progression to AIDS
MICA	Noncoding SNV near MICA, rs4418214-T	May affect HLA class I peptide presentation— linkage with protective HLA-B alleles	Enriched in HIV-1 controllers
PSORS1C3	rs3131018-A	May affect HLA class I peptide presentation	Enriched in HIV-1 controllers
ZNRD1	rs9261174-C	Possible interference in processing of HIV transcripts; influence ZNRD1 expression	Slower disease progression to AIDS
rs333: 32-bp deletion in the ORF (Δ32) found in persons of European descent	Truncated CCR5 protein; reduced co-receptor activity of R5 HIV strain
Promoter SNVs, haplotypes (HHA to HHG*2)	Altered CCR5 expression, e.g., HHE haplotype correlates with high CCR5 expression
rs1015164 G→A (34 kb downstream from CCR5 and close to CCRL2)	Increased expression of the lncRNA RP11-24-11.2, which corresponds to an antisense transcript that overlaps CCR5 (CCR5AS); results in increased CCR5 expression
rs1799864: SNV in ORF (64 V→I)	Linkage with polymorphisms in CCR5 promoter
rs3204849: SNV in ORF (167 Y→F)	SNV in linkage with CCR5 haplotype
rs2234358: G→T in the 3’ UTR	Trafficking of effector T cells and activation of NK T cells; minor HIV co-receptor
SNVs in ORF: rs3732379 (249 V→I) and rs3732378 (280 T→M)	Alleles bearing 249I and 280M reduce receptor expression and binding of fractalkine, the CX3CR1 ligand
rs2814778: Promoter SNV (–46T→C) found in persons of African descent	–46C/C associated with absent DARC expression (Duffy null), low neutrophil counts, and altered circulating chemokine levels as well as HIV binding to RBCs and trans-infection of HIV-1
Chemokines
CCL3L, CCL4L	Gene copy number of CCL3L and CCL4L	High numbers of CCL3L and CCL4L gene- containing segmental duplications correlated with high CCL3L and CCL4L levels	Gene copy number lower than population median associated with increased HIV-AIDS susceptibility and lower CD4+ T cell recovery during ART
CCL5	Promoter SNVs	Altered gene expression	Influenced HIV-AIDS susceptibility
CCL2	rs1024611: Promoter SNV (–2578 T→G)	–2578G allele: increased CCL2 expression and monocyte recruitment	–2578G/G associated with increased risk of developing HIV-1–associated dementia and faster AIDS onset

TABLE 208-7 Elements of the Immune Response to HIV Humoral immunity Neutralizing antibodies¶

Harrison's 22e, p.1586

Humoral immunity

TABLE 208-8 Characteristics of Tests for Direct Detection of¶

Harrison's 22e, p.1590

TEST	TECHNIQUE	SENSITIVITYa	COST/TESTb
Immune complex–dissociated p24 antigen capture assay	Measurement of levels of HIV-1 core (p24) protein in an EIA-based format following dissociation of antigen–antibody complexes by weak acid treatment	Positive in 50% of patients; detects down to 15 pg/mL of p24 protein	$1–2
	Target amplification of HIV-1 RNA via reverse transcription followed by PCR	Reliable to 20 copies/mL of HIV RNA
HIV RNA by bDNA	Measurement of levels of particle-associated HIV RNA in a nucleic acid capture assay employing signal amplification	Reliable to 50 copies/mL of HIV RNA	$75–150
	Target amplification of HIV-1 RNA via reverse transcription followed by T7 RNA polymerase	Reliable to 100 copies/mL of HIV RNA
HIV RNA by NASBA	Isothermal nucleic acid amplification with internal controls	Reliable to 80 copies/mL of HIV RNA	$75–150

TABLE 208-9 Association between High-Sensitivity CRP, Il-6, and d-Dimer with All-Cause Mortality in Patients with HIV…¶

Harrison's 22e, p.1591

MARKER	UNADJUSTED		ADJUSTED
	ODDS RATIO (FOURTH/FIRST)	P	ODDS RATIO (FOURTH/FIRST)	P
Hs-CRP	2.0	.05	2.8	.03
	8.3	<.0001	11.8
d-dimer	12.4	<.0001	26.5	<.0001

TABLE 208-10 Clinical Findings in the Acute HIV Syndrome General¶

Harrison's 22e, p.1592

General	Neurologic
Pharyngitis	Encephalitis
Headache/retroorbital pain	Myelopathy
Lethargy/malaise	Erythematous maculopapular rash
Nausea/vomiting/diarrhea

TABLE 208-11 NIH/CDC/IDSA 2024 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with¶

Harrison's 22e, p.1594

PATHOGEN	INDICATIONS	FIRST CHOICE(S)	ALTERNATIVES
Cryptococcus neoformans	Prior documented disease—primary prophylaxis not recommended in United States	Fluconazole 200 mg/d PO	Itraconazole 200 mg/d PO
	May stop secondary prophylaxis 1 year after initiation of therapy if CD4+ T cell count >100/μL, no evidence of active fungal infection, and HIV RNA levels suppressed for >3 months
Histoplasma capsulatum	Prior documented disease or CD4+ T cell count <150 μL and high risk (endemic area or occupational exposure)	Itraconazole 200 mg bid PO	Fluconazole 400 mg/d PO
	May stop prophylaxis after 1 year if CD4+ T cell count >150/μL and patient on effective ART for ≥6 months
Coccidioides immitis	Prior documented disease or positive serology and CD4+ T cell count <250/μL if from a disease endemic area. (For this indication prophylaxis can be stopped if CD4+ T cell count ≥250 for 6 months.)	Fluconazole 400 mg PO daily
Talaromyces (formerly Penicillium) marneffei	Prior documented disease Patients with CD4+ T cell counts <100 who live or stay in northern Thailand, Southern China, or Vietnam	Itraconazole 200 mg/d PO	Fluconazole 400 mg PO once weekly
	May stop secondary prophylaxis in patients on ART with CD4+ T cell count >100/μL for ≥6 months
Salmonella species	Prior recurrent bacteremia—primary prophylaxis not generally recommended	Based on sensitivity of initial infection
Bartonella	Prior infection	Doxycycline 200 mg/d PO
	May stop after 3–4 months of therapy and with a CD4+ T cell count >200/μL for >3 months and effective ART for at least 6 months	or Azithromycin 1200 mg weekly PO or Clarithromycin 500 mg bid PO
Cytomegalovirus	Prior end-organ disease—primary prophylaxis not recommended	Valganciclovir 900 mg once daily PO
	May stop secondary prophylaxis if CD4+ T cell count >100/μL for 6 months and no evidence of active CMV disease Restart if CD4+ T cells <100/μL
Immunizations Generally Recommended
All susceptible (anti-HBc– and anti-HBs– negative) patients	Hepatitis B vaccine: 3 doses
All susceptible (anti-HAV–negative) patients	Hepatitis A vaccine: 2 doses
All patients annually	Inactivated trivalent influenza virus vaccine 1 dose yearly
Annually or per updated CDC recommendations (www.cdc.gov/covid/vaccines/ immunocompromised-people.html)
All patients, preferably before CD4+ T cell count ≤200/μL Reimmunize persons initially immunized at a CD4+ T cell count <100/μL whose CD4+ T cell count then increases to >200/μL	Pneumococcal conjugated vaccine (15 or 20) 0.5 mL IM; if 15-valent is used, follow in 8 weeks or more by pneumococcal polysaccharide vaccine (23)
All patients 13–26 years of age	HPV vaccine; 3 doses
All patients with HIV who have potential for mpox exposure	Mpox vaccine (MVA-BN); 2 doses
All patients with HIV infection >18 years	Two doses of quadrivalent meningococcal conjugate vaccine
Age <18 years	Two-dose series of recombinant zoster vaccine (Shingrix) IM 2–6 months apart

TABLE 208-13 Causes of Bone Marrow Suppression in Patients with HIV Infection¶

Harrison's 22e, p.1604

DISEASES	MEDICATIONS
HIV infection Mycobacterial infections Fungal infections B19 parvovirus infection Lymphoma	Zidovudine Dapsone Trimethoprim-sulfamethoxazole Pyrimethamine 5-flucytosine Ganciclovir Interferon α Trimetrexate Foscarnet

TABLE 208-12 Characteristics of Immune Reconstitution Inflammatory Syndrome (IRIS) Paradoxical worsening of an existing…¶

Harrison's 22e, p.1604

Paradoxical worsening of an existing clinical condition or abrupt appearance of
a new clinical finding (unmasking) is seen following the initiation of antiretroviral
therapy
Occurs weeks to months following the initiation of antiretroviral therapy
Is most common in patients starting therapy with a CD4+ T cell count <50/μL who
experience a precipitous drop in viral load
Is frequently seen in the setting of tuberculosis, particularly when ART is started
soon after initiation of anti-TB therapy
Can be fatal

TABLE 208-14 Neurologic Diseases in Patients with HIV Infection HIV-1 infection¶

Harrison's 22e, p.1606

HIV-1 infection
Aseptic meningitis
HIV-associated neurocognitive disorders
(HAND), including HIV encephalopathy/AIDS
dementia complex
Myelopathy
Vacuolar myelopathy
Pure sensory ataxia
Paresthesia/dysesthesia
Peripheral neuropathy
Acute inflammatory demyelinating
polyneuropathy (Guillain-Barré syndrome)
Chronic inflammatory demyelinating
polyneuropathy (CIDP)
Mononeuritis multiplex
Distal symmetric polyneuropathy
Myopathy

Opportunistic infections
Toxoplasmosis
Cryptococcosis
Progressive multifocal
leukoencephalopathy
Cytomegalovirus
Syphilis
Mycobacterium
tuberculosis
HTLV-1 infection
Amebiasis
Neoplasms
Primary CNS lymphoma
Kaposi’s sarcoma

TABLE 208-15 Clinical Staging of HAND According to Frascati Criteria STAGE Asymptomatic Mild neurocognitive disorder…¶

Harrison's 22e, p.1607

STAGE	NEUROCOGNITIVE STATUSa	FUNCTIONAL STATUSb
Asymptomatic	1 SD below mean in 2 cognitive domains	No impairments in activities of daily living
	1 SD below mean in 2 cognitive domains
HIV-associated dementia	2 SD below mean in 2 cognitive domains	Notable impairments in activities of daily living

TABLE 208-16 Causes of Seizures in Patients with HIV Infection¶

Harrison's 22e, p.1608

DISEASE	OVERALL CONTRIBUTION TO FIRST SEIZURE, %	FRACTION OF PATIENTS WHO HAVE SEIZURES, %
HIV encephalopathy	24–47	7–50
	28
Cryptococcal meningitis	13	8
	4
Progressive multifocal leukoencephalopathy	1	20

TABLE 208-17 National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group TIS Staging System for…¶

Harrison's 22e, p.1612

PARAMETER	GOOD RISK (STAGE 0): ALL OF THE FOLLOWING	POOR RISK (STAGE 1): ANY OF THE FOLLOWING
Tumor (T)	Confined to skin and/ or lymph nodes and/or minimal oral disease	Tumor-associated edema or ulceration Extensive oral lesions GI lesions Nonnodal visceral lesions
	CD4+ T cell count ≥200/μL
Systemic illness (S)	No B symptomsa	B symptomsa present
	Karnofsky performance status ≥70	Karnofsky performance status <70
	No history of opportunistic infection, neurologic disease, lymphoma, or thrush	History of opportunistic infection, neurologic disease, lymphoma, or thrush

TABLE 208-18 Management of AIDS-Associated Kaposi’s Sarcoma Observation and optimization of antiretroviral therapy…¶

Harrison's 22e, p.1612

Observation and optimization of antiretroviral therapy
Single or limited number of lesions
Radiation
Intralesional vinblastine
Cryotherapy
Extensive disease; inadequate response to ART
Initial therapy
Interferon α (if CD4+ T cells >150/μL)
Liposomal daunorubicin
Subsequent therapy
Liposomal doxorubicin
Paclitaxel
Pomalidomide
Combination chemotherapy with low-dose doxorubicin, bleomycin, and
vinblastine (ABV)
Targeted radiation

TABLE 208-19 Initial Evaluation of the Patient with HIV Infection History and physical examination Routine chemistry…¶

Harrison's 22e, p.1615

History and physical examination
Routine chemistry and hematology
AST, ALT, alkaline phosphatase, direct and indirect bilirubin
Lipid profile and fasting glucose
CD4+ T lymphocyte count
Plasma HIV RNA level
HIV resistance testing
HLA-B5701 screening
RPR or VDRL test
Anti-Toxoplasma antibody titer
Urinalysis
PPD skin test or IFN-γ release assay
Mini-Mental Status Examination
Serologies for hepatitis A, hepatitis B, and hepatitis C
Immunization with pneumococcal polysaccharide; influenza; HPV as indicated
Immunization with hepatitis A and hepatitis B if seronegative
Counseling regarding natural history and transmission
Help contacting others who might be infected

TABLE 208-20 HIV Resources Available on the World Wide Web¶

Harrison's 22e, p.1616

CLINICALINFO.HIV.GOV	US-approved HIV treatment guidelines
HIV.GOV	Epidemiological data and prevention information

TABLE 208-21 Antiretroviral Drugs Licensed in the United States for the Treatment of HIV Infection DRUG a Nucleoside or…¶

Harrison's 22e, p.1617

DRUGa	INDICATION	DOSE IN COMBINATION	SUPPORTING DATA	TOXICITY
Nucleoside or Nucleotide Reverse Transcriptase Inhibitors
Lamivudine (Epivir, 2′3′-dideoxy-3′- thiacytidine, 3TC)	In combination with other antiretroviral agents for the treatment of HIV infection	150 mg bid 300 mg qd	In combination with zidovudine superior to zidovudine alone with respect to changes in CD4+ T cell counts in 495 patients who were zidovudine-naïve and 477 patients who were zidovudine-experienced; 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 zidovudine alone	Flare of hepatitis in HBV-co- infected patients who discontinue drug
Emtricitabine (FTC, Emtriva)	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 HBV-co-infected patients who discontinue drug, skin discoloration
Abacavir (Ziagen)	For treatment of HIV infection in combination with other antiretroviral agents	300 mg bid	Abacavir + zidovudine + 3TC equivalent to indinavir + zidovudine + 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)	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 HBV-co-infected patients who discontinue drug
Tenofovir alafenamide (Vemlidy)	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
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
For treatment of HIV infection in combination with other antiretroviral agents	600 mg qhs	Efavirenz + zidovudine + 3TC comparable to indinavir + zidovudine + 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
In combination with other antiretroviral agents in treatment-experienced 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
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 treatment- naïve individuals, except in patients with pretherapy HIV RNA levels >100,000 where it was inferior
Protease Inhibitors
Ritonavir (Norvir)	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)	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 zidovudine + 3TC in a study of 810 treatment-naïve patients; comparable to nelfinavir when given in combination with stavudine + 3TC in a study of 467 treatment- naïve patients	Hyperbilirubinemia, PR prolongation, nausea, vomiting, hyperglycemia, fat maldistribution, rash transaminase elevations, renal stones

TABLE 208-22 Combination Formulations of Antiretroviral Drugs¶

Harrison's 22e, p.1621

NAME	COMBINATION
ABC/3TC (generic)	Abacavir 600 mg/lamivudine 300 mg
Biktarvya	Bictegravir 50 mg/tenofovir alafenamide 25 mg/emtricitabine 200 mg
Cimduo	Tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg
Delstrigoa	Doravirine 100 mg/tenofovir disoproxil fumarate 300 mg/ lamivudine 300 mg
Dovatoa	Dolutegravir 50 mg/lamivudine 300 mg
Julucaa	Dolutegravir 50 mg/rilpivirine 25 mg
Stribilda	Elvitegravir 150 mg/cobicistat 150 mg/tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg

Table 208-23 . does not lead to a limited num- received alloge- HIV infection. is dealing with Patients initiating…¶

Harrison's 22e, p.1621

Symfi Loa	Efavirenz 400 mg/tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg
Triumeqa	Dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mg

TABLE 208-25 Indications for Changing Antiretroviral Therapy in Patients with HIV Infection a Less than a 1-log drop in…¶

Harrison's 22e, p.1624

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, but the treatment of HIV-
  infected 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.

TABLE 208-25 Indications for Changing Antiretroviral Therapy in Patients with HIV Infectiona

Less than a 1-log drop in plasma HIV RNA by 4 weeks following the initiation of
therapy
A reproducible significant increase (defined as threefold or greater) from
the nadir of plasma HIV RNA level not attributable to intercurrent infection,
vaccination, or test methodology
Persistently declining CD4+ T cell numbers
Clinical deterioration
Side effects

TABLE 208-24 Initial Combination Regimens Recommended for Most Treatment-Naïve Patients Regardless of¶

Harrison's 22e, p.1624

For people who do not have a history of using Carbotegravir-LA as PrEP:
Bictegravir + tenofovir alafenamide + emtricitabine (Biktarvy)
Dolutegravir + tenofovira + emtricitabineb
Dolutegravir + lamivudine (Dovato) only for those with HIV
RNA ≤ 500,000 copies/ml
For people who have a history of Carbotegravir-LA as PrEP, INSTI genotype
resistance testing should be performed; if starting prior to resistance testing
results:
Darunavir/cobicistat or darunavir/ritonavir + tenofovira + emtricitabineb