Matthew B. Goetz, M.D.
October 2011
MANAGEMENT OF HIV INFECTION
PATIENT EVALUATION (ADULTS)
Initial patient evaluation
Medical history: emphasis on opportunistic infections.
Constitutional symptoms, fever, weight loss; symptoms of depression
Mucocutaneous candidiasis
Pneumonia, gastrointestinal symptoms
STDs
Cervical Pap smear: date, results and history of treatment
Risk behavior: drug, alcohol & cigarette use, sexual activity
PE as directed by history; include genital and rectal examination for signs of STDs and (for women) routine gynecologic
examination
Laboratory and other tests.
CBC, chemistry, liver & lipid panels, G6PD, UA, CD4 count, HIV viral load
Antibodies to Toxoplasma gondii (B-III), CMV (B-III)
STDs: RPR (A-II), GC & chlamydia (B-II)
Baseline urinalysis and calculated creatinine clearance should be considered, especially in black patients, because
of an increased risk of HIV-associated nephropathy (B-II). Other high-risk persons include black persons, those
with CD4 cell counts <200 cells/L or HIV RNA levels >4000 copies/mL, those with diabetes mellitus,
hypertension, or HCV coinfection
Hepatitis: total HAV Ab, HBsAg, HbcAb, HBcAb (consider HBV DNA for isolated +HBcAb), HCV Ab (RNA if Ab+)
Cervical Pap smear (A-I)
PPD or Interferon-gamma release assay (IRA, i.e, Quantiferon Gold): date, results and history of treatment
CXR: only if clinically indicated (e.g, positive PPD or IGRA) (B-III)
EKG: if over 40 or clinically indicated
HIV genotypic resistance test (A-IIII)
Vaccines:
HAV (C-III), HBV (B-II) if not known to be immune
S. pneumoniae: benefit greatest if CD4 > 200; may repeat after 5 years (A-III)
Influenza: Yearly, all patients (A-III)
Prophylaxis for opportunistic infections:
PCP prophylaxis: if CD4 < 200 or (if no CD4 count available), there is a history of recent unexplained fevers,
diarrhea, weight loss, night sweats or thrush.
Toxoplasmosis prophylaxis: if CD4 < 100
MAC prophylaxis: if CD4 < 50
TB prophylaxis: if > 5 mm induration on PPD, recent, close exposure, or radiological evidence w/o symptoms
Behavioral advice: Sexual, environmental/occupational, pets, food and water, travel
Follow-up visit
Directed history and physical examination
Laboratory and/or other tests
Q 3 months (may be extended to 4 – 6 months for stable patients with low viral loads and high CD4+ counts who or
not on therapy): CBC, CD4 lymphocyte count, HIV viral load
STD screening and tuberculosis screening tests should be repeated periodically depending on symptoms and signs,
behavioral risk, and possible exposures (B-III)
Healthcare maintenance
Every visit:
 Screening high-risk behaviors (sexual activity, shared drug-injection equipment) (A-II), STD symptoms (A-I)
 Screen for symptoms of STDs (A-I).
 Counsel regarding risk reduction should be given at all health encounters, regardless of risk behaviors reported by
the patient or perceived risk on the part of the health care provider (A-III).
 Monitor for medication adherence (A-III).
Annual
 PPD (moderate – high-risk patients) (B-III)
 Cervical Pap smear (A-I); more frequent if not normal at baseline and 6 months thereafter
 STD screening (RPR, consider chlamydia and gonorrhea)
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 Anogenital HPV screening and anal Pap tests (C-III).
Monitoring with anti-retroviral therapy
New anti-retroviral regimen
Baseline: CD4, VL, CBC, chem7, liver, lipid panels.
Fasting glucose and lipid levels (A-IIII)
Urinalysis and calculated creatinine clearance prior to initiating treatment with tenofovir or indinavir (B-II)
2 week f/u visit: monitor adherence, regimen tolerability, side effects (LFTs with nevirapine)
4 - 6 week f/u visit: VL; CBC; chemistry 7, liver, lipid panels
Fasting glucose and lipid levels (A-IIII)
6 week f/u visit: Check CD4 & VL (obtained at week 4); repeat LFTs with nevirapine
Q 3 months: if satisfactory  VL; two weeks before visit, check CD4, VL, CBC
Stable antiretroviral regimen):
Q 3-4 months: CBC, CD4 lymphocyte count, HIV viral load
Q 6-8 months: Chemistry 7, liver, and lipid panels
Q 12 months: RPR, PPD (moderate – high-risk patients), Pap smear
Monitoring for metabolic complications
 Diabetes: monitor HbA1c q 6 months
 Lipids manage per NCEP Guidelines
 Bone densitometry: baseline and 2 years if on treatment or borderline result (i.e., T score -1 – -2.4); check
www.shef.ac/uk/frax/index.htm for risk calculation
 Baseline study in postmenopausal women aged ≥ 65 years, and in younger postmenopausal women and men
with ≥ 50 who have ≥1 risk factor for premature bone loss (B-III).
 Risk factors: ≥ 5 mg prednisone qd, androgen deprivation therapy, history of low trauma fracture
 Counseling: benefits of regular exercise and adequate calcium and vitamin D intake; risks
 Evaluation: Rule out and treat secondary causes such as hypogonadism, vitamin D deficiency (< 20 ng/ml of 250H vitamin D). Check calcium, albumin, TSH, testosterone, vitamin D
 Treatment: secondary causes (if any), if none then bisphosphonates.
CO-MORBIDITIES
Diabetes/Insulin Resistance
Mechanisms:
d4T, ddI, ZDV: mitochondrial toxicity
Protease inhibitors:  glucose reported in 3 – 17% of patients receiving protease inhibitors; less often with
atazanavir.
 adipocyte differentiation
 Glut-4 mediated glucose uptake
 ß cell responsiveness
Dysregulation of adiponectin, leptin and TNF-
Incidence: The incident rate of diabetes in HIV-infected patients receiving combination antiretroviral therapy has been
reported to be 4.7-5.7/1,000 patient years with rates up to four times higher than in HIV-seronegative patients
Management
Monitor for new or worse diabetes especially with PIs (BIII)
Counsel patients about signs of hyperglycemia
q 3–4 m fasting glucose during 1st yr of PI treatment (CIII)
Routine glucose tolerance tests not recommended (DIII)
Continue HAART unless DM becomes severe (BIII)
Lipodystrophy (peripheral fat wasting and central adiposity)
Cardiovascular
PI exposure associated with  risk of MI
RR of 1.16/year (95% CL 1.10 – 1.23)~ 2x  risk over a 5 year period (effect of smoking is far greater than that
of PI use)
Effect only partly explained by dyslipidemia
Not able to examine effect of individual agents
Effect is particularly significant for indinavir, (fos)amprenavir or the combination of lopinavir with ritonavir; no
effect seen with saquinavir or nelfinavir; data are insufficient for atazanavir, darunavir, tipranavir
NNRTI exposure not associated with  risk of MI
RR 1.05 (0.98 – 1.13)
NRTI exposure: although still controversial, abacavir or didanosine are likely to increase the risk of myocardial
infarction, especially among individuals with ? 20% risk of myocardial infarction over a 10 year period.
Absolute MI risk over 10 years per Framingham risk group
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2
10 year
risk
+ ABC
Increase
NNH*
(Risk/1000 pt-yrs)
(5 yrs)
<10%
1.0
2.9
1.9
105
10 - 20%
5.9
7.7
1.8
111
> 20%
15.9
32.5
16.6
12
* NNH = the number of persons who would need to receive ABC in the indicated risk stratum for 5
years per each predicted additional MI attributed to ABC use.
Dyslipidemia:  TG,  LDL,  HDL)
Incidence: reported with all protease inhibitors (other than unboosted atazanavir. Most frequent with TPV/r, IDV/r, LPV/r.
Also observed with NRTI (d4t > ZDV > others) and EFZ; NVP   HDL
Monitor: serum levels of cholesterol and triglycerides (preferably fasting) at 3-4 month intervals during PI therapy (CIII)?
Intervention: recommended for triglyceride levels > 750-1000 mg/dL and/or LDL cholesterol levels > 130 mg/dL (in
individuals without known coronary disease and with 2 or more coronary risk factors) or >160 mg/dL (in individuals
without known coronary disease and with fewer than 2 coronary risk factors).
 cholesterol
Statin if TG 200 – 500 (B-I)
Avoid niacin if on PIs or LD present (C-III)
Avoid bile-sequestering resins (C-III)
 TG (> 500)
For DM consider insulin sensitizers (metformin and TZDs)
Decrease or eliminate EtOH
Specific agents
Fibrates: 1st line therapy (B-I)
Niacin: avoid if on PIs or LD present (C-III)
Omega-3 fatty acid supplements: alternative Rx (C-III)
Statins: not 1st line therapy (C-III)
Kidney disease
Screening and initial evaluations
Principles extrapolated from the benefits of screening for stage I-II chronic kidney disease in diabetics, in which
identifying and treating patients with microalbuminuria (a urinary albumin-to-creatinine ratio  30 mg/g), macroalbuminuria
(an albumin-to-creatinine ratio of  300 mg/g), or overt proteinuria (a protein-to-creatinine ratio of  300 mg/g).
 All patients at the time of HIV diagnosis should be assessed for existing kidney disease with a screening urine
analysis for proteinuria and a calculated estimate of renal function (C-III).
 If there is no evidence of proteinuria at initial evaluation, patients at high risk for the development of proteinuric
renal disease (i.e., African American persons, those with CD4+ cell counts <200/L or HIV RNA levels >4000
copies/mL, and those with diabetes mellitus, hypertension, or hepatitis C virus coinfection) should undergo annual
screening (B-II). Renal function should be estimated on a yearly basis to assess for changes over time (B-II).
 Additional evaluations (including quantification of proteinuria, renal ultrasound, and potentially renal biopsy) and
referral to a nephrologist are recommended for patients with proteinuria of grade  1+ by dipstick analysis (roughly
correlates with 30 mg/dL or protein creatinine ratio >300 mg/g) or GFR <60 mL/min per 1.73 m2 (B-II).
Management
 With evidence of nephropathy, blood pressure should be controlled to a level no higher than 125/75 mm Hg (B-III),
with the initial preferential use of ACE inhibitors or ARBs for those patients with proteinuria (B-II). Calcium channel
blockers should be avoided in patients receiving protease inhibitors (D-II).
 Patients with HIVAN should be treated with HAART at diagnosis (B-II). HAART should not be withheld from
patients simply because of the severity of their renal dysfunction (B-III).
 Addition of ACE inhibitors, ARBs, and/or prednisone should be considered in patients with HIVAN if HAART alone
does not result in improvement of renal function (B-II).
Antiretroviral dosing and renal toxicities
 Give additional doses given after hemodialysis for drugs that are readily removed by dialysis (B-II).
 NRTIs should not be withheld in pts with  GFR for fear of the development of lactic acidosis (D-III).
 Tenofovir: Biannual monitoring of renal function, serum phosphorus, and urine analysis for proteinuria and
glycosuria (B-III) for patients in any of the following categories:
 GFR <90 mL/min per 1.73 m2
 Receipt of other medications eliminated via renal secretion (e.g., adefovir, acyclovir, ganciclovir, or cidofovir)
 Diabetes or hypertension
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 Use of ritonavir-boosted protease inhibitor regimen
PRINCIPLES OF THERAPY OF HIV INFECTION
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Ongoing HIV replication leads to immune system damage and progression to AIDS. True long-term survival free of
clinically significant immune dysfunction is unusual.
Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4+ T-cell destruction,
while CD4+ T-cell counts indicate the extent of HIV-induced immune damage.
Suppression of HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the
potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs
to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV
replication should be the goal of therapy.
The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of
combinations of drugs with which the patient has not been previously treated and that are not cross-resistant with
antiretroviral agents with which the patient has been treated previously.
Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum
schedules and dosages.
Effective antiretroviral drugs are limited in number and mechanism of action, and by cross-resistance. Therefore, any
change in antiretroviral therapy increases future therapeutic constraints.
Women should receive optimal antiretroviral therapy regardless of pregnancy status.
The same principles of antiretroviral therapy apply to both HIV-infected children and adults.
INITIAL THERAPY OF HIV (treatment-naïve patients)
Symptoms
Yes
No
No
Therapy
Yes (AI)
Yes (AI)
Yes (A/B-II) – Split vote 55% of Panel members for strong recommendation (A) and
45% for moderate recommendation (B)
No
> 500
Yes/Consider (B/C-III) – Split vote 50% of Panel members for moderate
recommendation (B) and 50% for optional recommendation (C)
No
> 350
Consider rate of CD4 decrease (e.g., <500 or 100 cell /yr) and VL (e.g., >100,000
 Other indications for initiating antiretroviral therapy:
 Pregnant women (AI)
 Patients with HIV-associated nephropathy (AII)
 Patients coinfected with HBV when treatment is indicated (AIII).
 Rapid decrease of CD4 count > 100 cell /yr (AIII)
 High VL (e.g., >100,000) (BII)
 Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should
understand the benefits and risks of therapy and the importance of adherence (AIII).
 Patients may choose to postpone therapy, and providers may elect to defer therapy, based on clinical and/or
psychosocial factors on a case-by-case basis.
Risks and benefits of early initiation of antiretroviral therapy in asymptomatic patients
Potential Benefits
Control of viral replication easier to achieve and maintain
Delay or prevent immune system compromise
Possible decreased risk of transmission
Potential Risks
Reduction in quality of life from adverse drug effects
Greater cumulative drug-related adverse events
Earlier development of drug resistance
Limitation in future choices of antiretroviral agents
Risk of dissemination of drug-resistant virus
Considerations in timing of therapy: Patient Factors
The degree of immunodeficiency (CD4 count)
Risk of disease progression (viral load)
Willingness to begin therapy
The likelihood of adherence
Considerations in choice of initial therapy
Co-morbidities: TB, liver disease, CVD, chemical dependency, psychiatric disease, or renal diseases
Adherence potential and dosing convenience
Potential adverse drug effects and drug-drug interactions
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CD4
Any
< 350
350 - 500
4
Gender
Pregnancy potential
Results of genotypic drug resistance testing
HLA B*5701 testing if considering abacavir.
INITIAL Antiretroviral regimens for treatment naïve patients: choose 2 NRTIs + one NNRTI or one PI
Preferred: 3TC & FTC are interchangeable
NRTI options: TFV/FTC (AI) - use TDF with caution in patients with renal insufficiency
NNRTI options: EFZ (AI)
PI options: ATV/rtv (AI) or DRV/r (AI)
II option: Raltegravir (AI)
Pregnancy: ZDV/3TC & bid LPV/r (AI)
Alternatives: 3TC & FTC are interchangeable
NRTI options: ABC/3TC (BI) – use ABC with caution if baseline VL >100,000 copies/mL or known high risk of
cardiovascular disease
NNRTI options:
EFV & ABC/3TC (BI)
RPV & ABC/3TC (BIII) – use RPV with caution if baseline VL >100,000 copies/mL
PI options:
ATV/r & ABC/3TC (BI)
fAPV/r qd or bid & ABC/3TC (BI) or TDF/FTC (BI)
DRV/r & ABC/3TC (BIII)
LPV/r qd or bid & & ABC/3TC (BI) or TDF/FTC (BI)
SQV/r & TDF/FTC (BI)
II options:
RAL & ABC/3TC (BIII)
Acceptable regimens
NRTI options: ZDV/3TC (CI)
NNRTI options
EFV & ZDV/3TC (CI)
NVP & ZDV/3TC (CI), TDF/FTC (CI) or ABC/3TC (CIII)
PI options
ATV & (ABC or ZDV)/3TC (CI)
ATV/r & ZDV/3TC (CI)
DRV/r & ZDV/3TC (CIII)
fAPV/r qd or bid & ZDV)/3TC (CI)
LPV/r qd or bid & ZDV)/3TC (CI)
II options:
RAL & ZDV/3TC (CIII)
Regimens that may be acceptable but more definitive data needed
MVC & ZDV/3TC (CIII)
RAL & ZDV/3TC (CIII)
SQV/r & (ABC or ZDV)/3TC (CIII)
DRV/r & ZDV/3TC (CIII)
Not recommended as initial therapy
Inferior efficacy
Toxicity
Insufficient data
ZDV/3TC/ABC
d4T/3TC
ZDV/3TC/TFV (BIII)
ddI /TDF (BII)
IDV or IDV/rtv
NNRTI + PI regimens
ddI/3TC
RTV as sole PI
Rtv-boosted PI monotherapy
Delavirdine
Enfuvirtide (T-20)
Nelfinavir
ETV
Tipranavir/rtv (BI)
ABC/ddI (BIII)
ZDV/3TC/ABC/TDF
ABC/TDF (BIII)
APV (unboosted) (BIII)
SQV (unboosted (BI)
Antiretroviral Regimens or Components That Should Never Be Offered At Any Time (all class E)
Monotherapy with NRTI or NNRTI
Dual NRTI regimens
Dual NNRTI regimens
Triple NRTI regimens (except ZDV/3TC/ABC and possibly ZDV/3TC/TFV)
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3TC/FTC (EIII), D4T/ZDV (EII), ddI/d4t (EIII), ddC/d4T (EIII), ddC/3TC
EFZ in pregnancy
NLV in pregnancy
APV solution: pregnancy, age < 4, renal or hepatic failure, use of MTZ or disulfiram (propylene glycol)
ATV/IDV ( bilirubin) (EIII)
SHORT-TERM THERAPY INTERRUPTIONS: Although treatment interruptions should be avoided, when necessary
(e.g., drug toxicity) all drugs should be stopped simultaneously if drugs have similar half lives or the patient has
severe or life-threatening toxicity. For patients taking efavirenz or nevirapine, where the half-life of these agents is
far longer than with other antiretroviral agents, therapy with nevirapine of efavirenz should be stopped 4 – 7 days
before other agents. Alternatively, a protease inhibitor can be substituted for nevirapine of efavirenz and all agents
can be stopped 2 – 3 weeks later.
MANAGEMENT OF TREATMENT FAILURE
Definition of treatment failure
Inadequate VL 
< 0.5 - 0.75 log at 4 weeks (CIII)
> 400 at 24 weeks or > 50 at 48 weeks (BIII).
VL rebound
Repeatedly > 400 - 5,000 after being < 50* (BIII)
> 3X increase from a detectable VL nadir* (BIII)
* Note that a VL <50 RNA copies/mL by the Amplicor HIV-1 Monitor® test is equivalent to < 75 copies/mL by
VERSANT HIV-1 RNA 3.0 Assay or < 80 copies/mL by the Nuclisens® assay
NOTES:
 Persistent low-level viremia (e.g., HIV RNA 50–200 copies/mL) does not necessarily indicate virologic failure or a
reason to change treatment.
 Some HIV RNA assays are associated with more frequent “blips” (i.e., the Taqman assay which is used at GLA)
and results should be interpreted with caution. It is not clear how to manage patients with persistent low-level
viremia; many experts would not change therapy and would follow the patient closely (CII).
Immunological (CIII) deterioration
New or recurrent HIV event after 3 months Rx
Consider quality and quantity of treatment options!
Contributions to Treatment Failure
Adherence: access to Rx, social factors, mental health, substance use
Tolerability: management of side effects
Pharmacokinetics: dosing and dietary schedule, drug-drug and drug-herbal interactions
Virological potency
Resistance
Treatment Failure: Patient Assessment
Review antiretroviral treatment history.
Assess adherence, tolerability, and PK issues.
Distinguish between 1st, 2nd or multiple Rx failures.
Perform resistance testing while on therapy.
Identify susceptible drugs and drug classes.
Guidelines for Changing Therapy after Virological Failure: Use the treatment history and past and current resistance
test results to identify active agents (preferably at least two fully active agents) to design a new regimen (AII). A fully
active agent is one likely to demonstrate antiretroviral activity on the basis of both the treatment history and
susceptibility on drug-resistance testing.
Prior Rx, pVL > 1000 & no resistance: Consider the timing of the drug resistance test and non-adherence
Continue same regimen or starting new regimen with resistance testing in 2 – 4 weeks (CIII)
Intensify by boosting with RTV (BII)
Change to a completely new regimen (CIII)
Prior treatment and drug resistance
A new regimen should include at least 2 and preferably 3 new drugs (BIII)
For drug-specific resistance, discontinue NNRTI, raltegravir and enfuvirtide to decrease additional drug mutations
Extensive prior treatment and drug resistance:
The goal is to maximally resuppress HIV RNA levels through use of newer agents (raltegravir, maraviroc, etravirine,
enfuvirtide [T-20])
If a new regimen that contains at least two fully active agents cannot be identified. It is reasonable to observe a
patient on the same regimen, rather than changing the regimen, depending on the stage of HIV disease (BII).
There is evidence from cohort studies that continuing therapy, even in the presence of viremia and the absence
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of CD4 T-cell count increases, decreases the risk of disease progression. Other cohort studies suggest
continued immunologic and clinical benefits if the HIV RNA level is maintained <10,000–20,000 copies/mL.
Extensive prior treatment and highly drug-resistant HIV: For some highly treatment experienced patients, maximal
virologic suppression is not possible. In this case, antiretroviral therapy should be continued with regimens designed
to minimize toxicity, preserve CD4 cell counts, and avoid clinical progression. There is no consensus on how to
optimize management for these patients
It is reasonable to observe a patient on the same regimen, rather than changing the regimen, depending on the
stage of HIV disease (BII). There is evidence from cohort studies that continuing therapy, even in the presence
of viremia and the absence of CD4 T-cell count increases, decreases the risk of disease progression, especially
if the VL is <10,000–20,000 copies/mL
In general, adding a single, fully active antiretroviral drug in a new regimen is not recommended because of the risk
of development of rapid resistance (BII).
However, in patients with a high likelihood of clinical progression (e.g., CD4 T-cell count <100) and limited drug
options, adding a single drug may reduce the risk of immediate clinical progression (CI).
Guidelines for Immunological Failure: Usually defined as persistent (after > 1 year of Rx), CD4 + of < 200 cells/L
Factors associated with immunologic failure:
CD4 count <200/mm3 when starting ART;
Older age;
Coinfection (e.g., HCV, HIV-2, HTLV-1, HTLV-2);
Medications
Antiretrovirals (i.e., ZDV, TDF + ddI)
Other medications; interferon, cancer chemotherapy, prednisone,
Persistent immune activation; and
Loss of regenerative potential of the immune system.
Management of immunological failure
Assessment:
Interfering medications
Untreated co-infections, e.g., HIV-2, HTLV-1, HTLV-2
Serious medical conditions, e.g., malignancy
Treatment
It is not clear that immunologic failure in the setting of virologic suppression should prompt a change in the
antiretroviral drug regimen.
No benefit has been demonstrated by adding a drug in the setting of viral suppression
No benefit from changing to theoretically more suppressive Rx or from an NNRTI to a PI-based regimen
No benefit from interleukin-2
THERAPEUTIC DRUG MONITORING (TDM)
Considerable variability in drug concentrations among patients who take the same dose
Relationship between the drug concentration and anti-HIV effect, and in some cases, toxicities.
Data best for PIs and NNRTIs
Relationships between plasma and intracellular concentrations of NRTIs not yet established
VIRAL RESISTANCE
Rate of development of resistance: determined by viral proliferation (108-10 virions/day with mutation rate of 3 x 10-5 at
each codon per cycle results in multiple mutations per codon per cycle of replication). Persistence of mutations is
related to the mutation rate (copying error frequency at the codon in question), cost of the mutation to the replicative
capability of the virus, drug potency (as reflected by its effect on viral dynamics), and complexity of the mutations
necessary for the emergence of a drug-resistant phenotype (rapid failure of 3TC or NVP monotherapy is preceded by
a single point mutation which leads to high level resistance to these agents).
Epidemiology: in the mid 1990’s up to 10% of newly infected patients have high-level ZDV-resistance.
Susceptibility testing:
Genotypic Assays: Sequence based assays evaluate gag, pol, and gag cleavage site by direct sequencing (e.g.,
Virco VircoGENTM assay) or by Micro-chip technology (Affymetrix GeneChipTM assay ). Point mutation assays
(e.g., Line Probe assay (LiPaTM assay)) interrogate for presence of specific mutations.
Advantages : Mutations may precede phenotypic resistance, results more rapidly available, less expensive.
Disadvantages : Results may not correlate with phenotype, expert interpretation of mutations required,
insensitive for minor species, must be optimized to detect insertional mutations
Phenotypic Assays:
Original Susceptibility Assays: reduction of plaque (syncytia) formation or PBMC growth inhibition.
Recombinant Assays: Antivirogram TM assay (Virco), ViroLogic assay
Advantages : Direct measure of susceptibility, easier to interpret
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Disadvantages: Clinically significant cutoff values are undefined, may underestimate in vivo resistance,
insensitive for minor species
Multiple drug resistance: mechanisms
Nucleosides
Multiple conventional mutations (ZDV, 3TC, ddN)
Single mutations (151M, 69S-[X-X])
Mutations to one drug can modulate resistance to others (e.g., M184V)
Non-nucleosides and Protease Inhibitors
Single mutations may => narrow resistance
Multiple mutations may => broad resistance
Persistence of Resistance
Resistance often difficult to detect in plasma if therapy is stopped
Resistant virus usually less fit
Overgrowth by wild-type virus
Resistant pro-virus persists (archived) within long-lived, HIV-infected cells which harbor replication-competent virus
Use of Resistance testing: note that test requires a viral load >500 - 1000 HIV RNA copies/mL
Treatment naïve patients
When patients enter into care if treatment is to be initiated immediately (BIII) or if therapy is to be deferred (CIII)
A genotypic assay is generally preferred in treatment naïve patients (AIII)
Treatment experienced patients
Virologic failure (i.e., viral load >1,000) during HAART to assist in selecting a new regimen (AI). In persons with
>500 but <1000 copies/mL, testing may be unsuccessful but should still be considered (BII).
Resistance testing should be performed while on therapy or within 4 weeks thereafter (AII)
Pregnancy: genotypic testing should be done for all pregnant women prior to the initiation of antiretroviral therapy (AIII)
and for those with a f viral load > 1000 copies/mL while on therapy (A1)
Choice of assay
 Genotypic testing is recommended as the preferred resistance testing to guide therapy in patients with suboptimal
virologic responses or virologic failure while on first or second regimens (AIII).
 Addition of phenotypic testing to genotypic testing is generally preferred for persons with known or suspected
complex drug resistance mutation patterns, particularly to protease inhibitors (BIII).
PREGNANCY:
Principles: Use of antiretroviral prophylaxis has been shown to provide benefit in preventing perinatal transmission even
for infected pregnant women with HIV-1 RNA levels <1,000 copies/mL. In a meta-analysis of factors associated with
perinatal transmission among women who had infected infants despite having HIV-1 RNA <1,000 copies/mL at or
near delivery, transmission was only 1.0% among women receiving ZDV prophylaxis compared to 9.8% among those
receiving no antiretroviral treatment.

Because ZDV benefit is observed regardless of maternal HIV-1 RNA level and because transmission may occur
when HIV-1 RNA is not detectable, HIV-1 RNA should not be the determining factor in decisions regarding use of
ZDV chemoprophylaxis against perinatal transmission.

Prophylactic use of ZDV-monotherapy in pregnant women with low viral load and high CD4+ T cell counts prevents
perinatal transmission.

For pregnant women not currently receiving antiretroviral therapy, decision-making regarding initiation of therapy
should be the same as for non-pregnant individuals, with the additional consideration of the potential impact of such
therapy on the fetus and infant.

For pregnant women currently receiving antiretrovirals, decisions regarding alterations in therapy should use the
same parameters as for non-pregnant individuals.

Use of the 3-part ZDV chemoprophylaxis regimen (pre-partum intrapartum and therapy of the newborn), alone or in
combination with other antiretrovirals, should be discussed with and offered to all infected pregnant women for the
purpose of reducing perinatal transmission risk.

HIV-infected women in the U.S. should not breastfeed regardless of their antiretroviral therapy.
Regimens that should not be used during pregnancy: EFZ (teratogenic), NFV, fAPV solution
Maternal-child transmission:
Original ZDV Regimen: simpler regimens have also been shown to be beneficial
Antepartum
ZDV (500 – 600 mg qd in 2 – 5 divided doses), from 14-34 weeks gestation until delivery.
Intrapartum
During labor, IV ZDV in a 1-hour loading dose of 2 mg/kg, followed by a continuous
infusion of 1 mg/kg/hour until delivery.
Postpartum
po ZDV syrup at 2 mg/kg q 6 hour to the newborn for the first 6 weeks of life, beginning at
8-12 hours after birth. Can substitute 1.5 mg/kg IV q 6 hours).
Nevirapine: single intra-partum dose + single dose to newborn effective but results in maternal NRTI resistance.
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PIs: optimal levels of several PIs may not be achieved in pregnancy, especially in the third trimester, although the clinical
relevance of this is unknown. Once-daily LPV/r dosing is not recommended in pregnancy, because there are no data
to address adequacy of blood levels with this dosing regimen (BII).
POST-EXPOSURE HIV PROPHYLAXIS
Risk: The overall risk of HIV seroconversion is 0.3% following a needlestick injury from a source patient who is HIVinfected. The risk of HIV seroconversion after a mucosal exposure is substantially less.
Risk factor
Adjusted odds ratio
(95% Confidence limits )
Deep injury
15
(6.0–41)
Visible blood on device
6.2
(12.2–21)
Terminal illness in source patient
5.6
(2.0–16)
Needle in artery or vein
4.3
(1.7–12)
Postexposure use of zidovudine
0.19
(0.06–0.52)
CDC recommendations 2005: for exposure to potentially infectious fluids materials, e.g., blood, plasma, tissue, semen,
vaginal secretions, cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids.
Percutaneous exposure
Source material
Antiretroviral regimen
Less severe
HIV Class I
Recommend 2 drug PEP
HIV Class II
Recommend 3 drug PEP
Source known, but HIV? Consider 2 drug PEP if + risk
Unknown source
No PEP or 2 drug PEP
HIV-Negative
No PEP
More severe
HIV Class I
Recommend 3 drug PEP
HIV Class II
Recommend 3 drug PEP
Source known, but HIV? Consider 2 drug PEP if + risk
Unknown source
No PEP or 2 drug PEP
HIV-Negative
No PEP
Mucous membrane or non-intact skin
Source material
Antiretroviral regimen
Small volume
HIV Class I
Consider 2 drug PEP
HIV Class II
Recommend 2 drug PEP
Source known, but HIV? No PEP
Unknown source
No PEP
HIV-Negative
No PEP
Large volume
HIV Class I
Recommend 2 drug PEP
HIV Class II
Recommend 3 drug PEP
Source known, but HIV? No PEP or 2 drug PEP
Unknown source
No PEP or 2 drug PEP
HIV-Negative
No PEP
Less severe = solid needle and superficial injury
More severe = large-bore hollow needle, deep puncture, bloody device, or needle used in patient’s artery or vein
Class I = patients with asymptomatic HIV infection or known low viral load (<1,500 RNA copies/mL)
Class II = patients with symptomatic HIV infection, AIDS< acute seroconversion, or known high viral load.
Recommended PEP
NRTI backbone: (ZDV, d4T or TFV) & (3TC or FTC)
PI-based: LPV/r (or ATV/r, fAPV, fAPV/r)
NNRTI-based: EFZ (contraindicated in pregnancy)
AVOID use of nevirapine. Fatal hypersensitivity reactions have been reported.
Two versus three drugs: The recommendation for a three-drug HAART regimen is based on the assumption that
the maximal suppression of viral replication afforded by HAART will provide the best chance of preventing
infection in a person who has been exposed.
2 drug PEP: zidovudine# & lamivudine (Combivir™) or tenofovir#& emtricitabine (Truvada™)
3 drug PEP
Recommended regimens
Efavirenz* plus tenofovir & emtricitabine (Truvada™); Atripla™ contains efavirenz, tenofovir
NNRTI-based
and emtricitabine
Protease inhibitor
Atazanavir plus ritonavir plus tenofovir & emtricitabine (Truvada™)
Alternative regimens (GLA)
NNRTI-based
Efavirenz* plus either zidovudine & lamivudine (Combivir™) or lamivudine & abacavir
(Epzicom™)**
Protease inhibitor
Atazanavir plus zidovudine & lamivudine (Combivir™)
Protease inhibitor
Lopinavir/ritonavir (Kaletra™) plus tenofovir & emtricitabine (Truvada™), zidovudine &
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lamivudine (Combivir™) or lamivudine & abacavir (Epzicom™)**
* Efavirenz is a CLASS D AGENT in pregnancy (Positive Evidence of Fetal Risk). Do not use in pregnancy,
especially during the first trimester or in women of child-bearing potential who are not using effective
contraceptives.
 Abacavir-containing products should not be used as post-exposure prophylaxis unless B*5701 testing
has been previously performed and HLA B*5701 has been shown to be absent. Persons with HLA
B*5701 have a 60% risk of developing hypersensitivity reactions which can be severe and fatal.
 Post-exposure prophylaxis with nevirapine is CONTRAINDICATED. Fatal hypersensitivity reactions occur.
Antiretroviral resistance and selection of post-exposure prophylaxis
 An HIV strain is more likely to be resistant to a specific antiretroviral agent if it is derived from a patient who has
had viremia (HIV viral load > 500) for 3 – 6 months while receiving antiretroviral therapy.
NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS: inhibit reverse transcriptase
through competition with the host’s natural intracellular nucleotide pool. If incorporated into the subsequent viral DNA,
each of these agents leads to chain elongation termination. Seven of the agents are nucleoside analogues while one,
tenofovir, is a nucleotide in product form. The nucleosides to which these agents can substitute as follows:
Nucleoside
nRTI inhibitor
Adenosine: Purine
didanosine, tenofovir
Guanosine: Purine
abacavir
Cytosine: Pyrimidine
emtricitabine, lamivudine, zalcitabine
Thymidine: Pyrimidine
stavudine, zidovudine
Storage and shipping considerations: None
PK considerations:
FTC*
ABC ddI
3TC
d4T
TFV
ZDV
Bioavailability (%)
93
83
33 - 43
86
86
25
64
Plasma t½ (hr)
10
1.5
1.3 - 1.6
5-7
1.5
12 - 14 0.5 - 3
Intracellular t½ (hr)
39
3.3
25 - 40
12
3.5
10 - 50 3
Protein Binding (%) < 4
50
<5
< 36
Scant
< 7.2
< 38
Metabolism**
OX
AD
Renal
Renal
Renal
Renal
GLUC
GLUC GT
50%
50%
** OX = oxidation, GLUC = glucuronidation, AD = Alcohol dehydrogenase, GT = glucuronyl transferase
Class toxicities: rare occurrence of hepatic steatosis and lactic acidosis (estimated incidence of 1.3 cases per 1000
person-years of NRTI exposure).
Risk factors: greatest with ddI > d4T >ZDV, ABC, 3TC, TFV. Also female gender, obesity and prolonged use.
Presentation: Often non-specific. May include otherwise unexplained onset and persistence of abdominal distention,
nausea, abdominal pain, vomiting, diarrhea, anorexia, generalized weakness, weight loss, and hepatomegaly.
Treatment:
Suspend antiretroviral treatment (BIII).
Bicarbonate infusions and hemodialysis
Anecdotal reports of success with high doses of riboflavin. co-enzyme Q, carnitine and thiamin.
Some patients have tolerated rechallenge with a new NRTI-containing regimen.
Other toxicities:
Drug
Most common side effects*
abacavir
hypersensitivity reaction, nausea, fever/chills, headache, rash
didanosine
peripheral neuropathy, headache, pancreatitis
emtricitabine
headache, diarrhea, nausea, rash, hyperpigmentation
lamivudine
headache, malaise/fatigue, anorexia, dizziness, nausea, rash
stavudine
peripheral neuropathy, headache, rash, diarrhea, pancreatitis
tenofovir
nausea, diarrhea, vomiting, flatulence
zalcitabine
peripheral neuropathy, rash, pancreatitis, stomatitis
zidovudine
bone marrow suppression, headache, gastrointestinal intolerance, insomnia
* Each agent has lactic acidosis as a potential serious complication of therapy.
Abacavir (ABV, 1592, Ziagen™): guanosine analog. No drug-drug interactions, but EtOH  40%  serum levels.
Dosage: 300 mg q 12 hours,  food. 83% bioavailable. Metabolized by alcohol dehydrogenase and glucuronidation
(rifampin may  ABV levels by inducing glucuronidation). T½ ~ 1°. Good CSF penetration. Available in 300 mg
tablets and combined with zidovudine and lamivudine (300 mg ZDV/150 mg 3TC/300 mg ABC taken qd – Trizivir™)
or lamivudine (300 mg 3TC/600 mg ABC taken qd - Epzicom™).
Renal dosing: dosing unaffected by renal failure.
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Hepatic Impairment:  dose to 200 mg bid in patients with clinical or histological evidence of cirrhosis and mild
hepatic impairment (Child-Pugh score 5 to 6) is 200 mg twice daily; requires use of abacavir oral solution (10 mL
twice daily). Contraindicated in cirrhotic patients with moderate to severe hepatic impairment.
Toxicity:
Hypersensitivity reactions: Test for presence of HLA B*5701 prior to use; if not previously done, HLA B*5701 testing
should also be done in persons resuming abacavir after a treatment interruption (even if abacavir was previously
tolerated). Presence of HLA B*5701 strongly predictive for development of hypersensitivity reaction; true
hypersensitivity reaction is extremely uncommon in the absence of HLA B*5701. Hypersensitivity reactions
occur in <3% of patients at a median of 9 days after drug initiation (range 3 – 42 days, usually within 4 weeks).
Reaction manifest by fever, malaise, nausea and vomiting, mouth or throat lesions, conjunctivitis and respiratory
symptoms with or without morbilliform rash. Reaction abates within hours of drug discontinuation. DO NOT
RECHALLENGE!. Re-challenge has been associated with severe reactions; fatalities may occur. All
reintroduction of abacavir should be undertaken only if B*5701 is absent, with caution and only if
medical care can be readily accessed. Reactions 50% less frequent in non-whites;1.8 times more frequent
with < 50 CD4 cells (HOPS)
Cardiovascular risk: Association found between current use of abacavir and increased rate of myocardial infarction,
especially among individuals with a more than 20% risk of myocardial infarction over a 10 year period.
Absolute MI risk over 10 years per Framingham risk group
10 year
risk
No ABC
+ ABC
Increase
NNH*
(Risk/1000 pt-yrs)
(5 yrs)
<10%
1.0
2.9
1.9
105
10 - 20%
5.9
7.7
1.8
111
> 20%
15.9
32.5
16.6
12
* NNH = the number of persons who would need to receive ABC in the
indicated risk stratum for 5 years per each predicted additional MI attributed to
ABC use.
Didanosine (ddI, dideoxyinosine, Videx™): adenosine analogue. 35% oral bioavailability in buffered environment. 20%
CSF penetration. Acid labile. 50% renal excretion;  dose with Crcl < 25, 75%  dose with hemodialysis. 25-40°
intra-cellular t1/2.  dose when given with tenofovir. Avoid co-administration with ribavirin
Dosage: Available as powder (100, 167, 250 mg), or enteric coated capsules (125, 200, 250, 400 mg). Except when
taken with tenofovir (see below), all formulations should be taken either >½ hour before or >2 hours after eating.
Dosing options are 200 mg bid (tablets) or 400 mg qd (enteric coated capsules); reduce dose to 125 mg bid if weight
< 60 kg (250 mg qd enteric coated capsules).  dose if powder used. Decreases indinavir, dapsone,
delavirdine, INH, itraconazole, and ketoconazole absorption; separate doses by 2 hours.
Drug-drug interactions
Tenofovir. Give 250 EC ddI preparation with food (≤400 kcalories, ≤20% fat) when TFV also used (TFV
increases ddI levels)or 200 mg (adults weighing <60 kg). Dose not defined in persons with CrCl < 60.
Ribavirin: Increased ddI toxicity when used with ribavirin.
Oral ganciclovir: a/w  ddI levels.
Toxicity: dose-related neuropathy (10%), pancreatitis (2%; risk factors include use of hydroxyurea, allopurinol), diarrhea
(15%). Intracellular levels of active metabolite are increased when co-administered with ribavirin may cause or
worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and
peripheral neuropathy. Association found between current use of ddI and increased rate of myocardial infarction.
Prolonged exposure also associated with noncirrhotic portal hypertension with esophageal varices.
Emtricitabine (Emtriva™, FTC): NRTI; active vs HIV and HBV. Phase I => 1.5 log  VL.
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Dosage: 200 mg qd dosing. Also co-formulated with tenofovir (300 mg TFV/200 mg FTC taken qd – Truvada™). May
be taken with or without food. No effect on CYP450 enzymes. Renal excretion – requires dose adjustment.
Resistance: Resistance via M184V (same as for lamivudine).
Toxicity: Adverse effects no more common than in control groups except for  hyperpigmentation on palms and soles.
Lamivudine (3TC, Epivir™): dideoxy analog of cytidine. Renal excretion. 12° intra-cellular t1/2.
Dosage: 150 mg bid  food; reduce dose with weight < 50 kg (2 mg/kg bid) and to 150 mg qd with Crcl 26 – 49, to 100
mg q 24° for CrCl 10 – 25 and 25 – 50 mg q 24° for CrCl < 10 or hemodialysis. Available in 150 tablets and combined
with zidovudine and abacavir (300 mg ZDV/150 mg 3TC taken bid– Combivir™), zidovudine and abacavir (300 mg
ZDV/150 mg 3TC/300 mg ABC taken bid – Trizivir™), or abacavir (300 mg 3TC/600 mg ABC taken qd - Epzicom™).
Resistance: M184V is usual route of resistance (same as for emtricitabine). Presence of M184V   viral fitness, 
ZDV/d4T/TFV resistance and maintenance of small amount of antiretroviral activity.
Toxicity: Slight increased frequency of headache, neutropenia and anemia. Rebound transaminitis after discontinuation
in HBsAg(+) patients.
Stavudine (2',3' didehydro-2',3'-dideoxythymidine, d4T, Zerit™): Adequate CSF penetration. Less active when combined
with zidovudine. 50% renal excretion. 3-5° intra-cellular t1/2.
Dosage: May be taken with meals. 60 kg = 40 mg q 12, < 60 kg = 30 mg q 12. Reduce dose 50% for creatinine
clearance < 60 and 75% for Crcl< 30 or hemodialysis. Antagonizes activity of ZDV, do not combine these drugs!
Toxicity: Peripheral neuropathy; also anemia, hepatitis and nausea. Rare pancreatitis. Rare rapidly ascending
neuromuscular weakness mimicking Guillain-Barré Syndrome; often associated with lactic acidosis. Do not coadminister ddI and d4T during pregnancy.
Tenofovir (Viread™, PMPA): Nucleotide RTI; intracellular T½ = 15 – 50°. Active vs. HIV-1, HIV-2, HBV. Competes with
dATP. No metabolism via CYP450 system. Eliminated by glomerular filtration and active tubular secretion.
Potential  concentrations with agents that decrease tubular secretion, e.g. ritonavir; may result in bi-directional
increases in cidofovir, ganciclovir and valganciclovir concentrations.
Resistance: Selected K65R mutation   resistance to all NRTIs other than ZDV; K65R antagonizes effects of TAMS
on ZDV-R
Dosage: 300 mg qd;  absorption with food. Also co-formulated with emtricitabine (300 mg TFV/200 mg FTC taken qd –
Truvada™).  dosing to q 48° for Cr Cl < 50.
Drug-drug interactions:
Didanosine. Decrease ddI dose (see ddI recommendations)
Atazanavir: Tenofovir Cmin increased by atazanavir (22%); atazanavir concentration decreased by tenofovir.
TFV recommended dose unchanged; use rtv-boosted atazanavir; note that this  30%  [TFV].
Lopinavir/rtv: Tenofovir Cmin increased by lopinavir/ritonavir (51%). No dosage change).
Activity: Active vs. HIV-1, HIV-2, HBV. Resistance via K65R, T69S insertion, and presence of > 3 TAM including either
M41L or L210W (no TAM effect if M41L and L210W absent). Active versus M184V, Q151M, K70R. Do not use
ddI/3TC/TFV or 3TC/ABC/TFV regimens. Increased rate of virological failure reported in treatment naïve patients
when compared to 3TC/ABC/EFZ regimens (for 3TC/ABC/TFV) or expected results from more potent regimens
(ddI/ABC/TFV).
Toxicity: mild-moderate headache, nausea, diarrhea, flatulence. Osteomalacia in animals given high doses. After 144
weeks or Rx, lumbar spine BMD decreased more with TFV/3TC/EFZ than with d4T/3TC/EFZ (-2.2% vs -1.0%). Hip
BMD changes did not differ between TFV and d4T.
Zalcitabine (ddC, dideoxycytidine, HIVID™). 20% CSF penetration. 70% renal excretion. 3° intra-cellular t1/2. No longer
distributed in the United States as of 2006
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs): non-competitive inhibitors.
Storage and shipping considerations: None
Common toxicities: rash. Potentially fatal cases of Stevens-Johnson syndrome have been reported.
PK considerations: Multiple drug-drug interactions. See separate PK section for interactions with other NNRTIs, PIs,
rifampin, and rifabutin.
Contraindicated drugs: see individual agents
Delavirdine (DLV; Rescriptor™): Highly protein bound; poor CSF penetration. Renal excretion of hepatic metabolites.
6° intra-cellular t1/2.
Dosage: two 200 mg tablets po tid. Can be given  food but not with ddI, proton pump inhibitors or antacids. Absorption
requires gastric acidity. Non-linear pharmacokinetics ( conc. with  dose).
Drug interactions: Inhibits cytochrome CYP3A. Markedly  AUC with phenytoin, phenobarbital, or carbamazepine.
DLV  200%  level of clarithromycin and smaller  of dapsone, dihydropyrides, and warfarin.  sildenafil AUC (do
not exceed 25 mg sildenafil over 48 hours).
Avoid with: simvastatin, lovastatin, astemizole, terfenadine, H2 receptor antagonists, proton pump inhibitors, cisapride,
alprazolam, midazolam, triazolam, ergot derivatives, amphetamines, nifedipine, phenytoin, carbamazepine,
phenobarbital. Also increases serum concentrations of quinidine and warfarin. Do not use with rifabutin, rifampin.
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Toxicity: Rash (18%), headaches, abnormal transaminases.
Efavirenz (EFV, DMP-266, Sustiva™):
Dosage: three 200 mg tablets or one 600 mg tablet po qd;  absorption and toxicity with high fat meals. Store at room
temperature. Drug levels not affected by liver disease.
Drug interactions: metabolized by CYP3A4. See separate PK section for interactions with other NNRTIs, PIs, rifampin,
and rifabutin. Efavirenz is a mild - moderate induction of CYP3A4 production but also inhibits CYP3A4 activity. EFV
does not affect azithromycin AUC. EFV  37%  ethinyl estradiol AUC, 34%  clarithromycin – 14 OH AUC (?
significance), 40%  clarithromycin AUC. Fluconazole  17%  EFV AUC (no data with other azoles). Although no
data, expect  EFV AUC with phenobarbital, phenytoin. Significant  methadone levels.
Drugs to be avoided: astemizole, terfenadine, cisapride, midazolam, triazolam, ergot derivatives. Carefully monitor
warfarin.
Toxicity: dizziness, headaches,  concentration, insomnia, rash ( in children). CNS effects less with q hs dosing. Side
effects generally resolve within 2 – 4 weeks. CLASS D AGENT in pregnancy (Positive Evidence of Fetal Risk).
Do not use in pregnancy, especially during the first trimester or in women of child-bearing potential who are not
using effective contraceptives.
Etravirine (Intelence, TMC-125):
Pharmacokinetics: 99.9% protein bound, T1/2 (terminal 41 (±20) hrs; undergoes metabolism by CYP3A4, CYP2C9, and
CYP2C19; induces CYP3A4, inhibits CYP2C9 and CYP2C19
Dose: two 100 mg pills bid with/after meals. No dosage adjustment for patients with mild to moderate hepatic
impairment. Adequately evaluated in individuals with severe hepatic impairment (Childs class C). No dosage
adjustment is necessary for patients with renal impairment. Not expected to be dialyzable.
Drug-drug interactions: best safety & efficacy data is when used concomitantly with NRTIs and darunavir/rtv. Marginal
effect on raltegravir PK.
Do not administer with:
NNRTIs: Efavirenz, nevirapine, delavirdine
PIs: Without adjunctive ritonavir: any. Regardless of adjunctive ritonavir: tipranavir, atazanavir, fosamprenavir.
Also do not use with full dose ritonavir
Other: carbamazepine, phenobarbital, phenytoin, clarithromycin, rifampin, rifapentine
Use with caution:
Rifabutin (use only if co-administered with darunavir/ritonavir or saquinavir/ritonavir)
Lopinavir/ritonavir: increase in AUC of etravirine by 85% compared to Phase III trials
Anti-arrhythmics (monitor drug concentrations, if available): amiodarone, bepridil, disopyramide, flecainide,
lidocaine (systemic), mexiletine, propafenone, quinidine
Dexamethasone: increase etravirine concentrations
Cyclosporine, sirolimus, tacrolimus
Azoles: fluconazole ( ETV), itraconazole ( ETV,  itra), posaconazole ( ETV), voriconazole (ETV,  vori).
Statins:
Pravastatin & rosuvastatin OK
Atorvastatin, lovastatin, fluvastatin, simvastatin: may require statin dose titration to lipid response.
Use with maraviroc: dose adjustment of maraviroc (MVC) is needed; no dose adjustment for ETVis necessary
When MVC is co-administered with ETV with a boosted PI, the recommended dose of MVC is 150 mg b.i.d
When MVC is co-administered with ETV without a boosted PI, the recommended dose of MVC is 600 mg b.i.d.
Toxicity rash (no overlap with other NNRTI-induced rashes, more common in women, may progress to Stevens-Johnson
Syndrome), nausea,  TG, ± LFTs, headache
Resistance: Resistance associated mutations (RAMs) include V90I, A98G, L100I, K101E/P, V106I, V179D/F,
Y181I/C/Y/V, G190A/S. In Duet trials, VS < 50 was 75% with no RAMS, 60% with 1 RAM, 58% with 2 RAMS, 42%
with 3 RAMS 25% with 4 RAMS and 13% with 5 RAMS.
Nevirapine (NVP; Viramune™): Not active against HIV-2. Good CSF penetration. Renal excretion of glucuronidated
metabolites. 25-30° intra-cellular t1/2.
Dose: 200 mg qd x 2 weeks, then either one extended-release 400 mg tablet qd or 200 mg immediate-release tablets
bid. Do not increase dose if rash or clinical hepatitis is present. Can be taken  meals, antacids or ddI.
Drug interactions: Maximal induction of CYP3A family of P450 system after 2 - 4 weeks; potential interactions with oral
contraceptives, triazolam, midazolam, methadone. No significant interact with macrolides. Avoid with ketoconazole.
Use: Do not use if pre-nevirapine CD4+ count > 250 (women) or > 400 (men )due to  rate of hypersensitivity reactions.
Symptomatic hepatic events have not been reported with single doses of nevirapine given to mothers or infants for
prevention of perinatal HIV infection
Toxicity: hypersensitivity reaction with potentially life-threatening rash and hepatotoxicity (~0.3%); usually within first 12
weeks of treatment.
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Rash: 5% of pts. develop significant rash, and 1% significant hepatitis; risk of severe rash may be several times
higher in women than men.. Patients who experience mild to moderate rash (without constitutional symptoms)
during the 200mg QD, 14 day lead-in period should not have their nevirapine dose increased to the
recommended 200mg BID until the rash resolves. If the rash does not resolve within 28 days, then an
alternative agent should be used.
Hypersensitivity: Patients with rash-associated transaminase elevations should be permanently discontinued from
nevirapine. Permanently D/C with severe rash especially if accompanied by hypersensitivity reaction (fever,
mucositis, myalgias, arthralgia, lymphadenopathy, eosinophilia, renal dysfunction, granulocytopenia or
increased transaminases (>5 X ULN)). Rash present in 50% of pts with severe hepatotoxicity. Not
recommended in women with pre-nevirapine CD4+ count > 250.
Hepatotoxicity:
Nevirapine should not be administered to patients with moderate or severe hepatic impairment (Child-Pugh
Class B or C). Increased levels of nevirapine may be observed in patients with serious liver disease.
Liver transaminases should be checked immediately in any patient receiving nevirapine who develops a rash.
Patients with hepatitis B or C co-infection may also have increased risk of clinical hepatitis.
Nevirapine should not be restarted after severe hepatic, skin, or hypersensitivity reactions.
Elevation of transaminases may also occur after week 18. Most of these cases are asymptomatic and
treatment may be continued without adverse clinical consequences
Rilpivirine (RPV, Edurant™): Not active against HIV-2. 99.7% protein bound. Elimination: 85% feces and 6.1% urine.
Metabolism: undergoes oxidative metabolism by CYP3A4, minor via 2C19. t1/2 50°. Rilpivirine does not have an
effect on the exposure of other drugs metabolized by CYP enzymes.
Dose: 25 mg qd. The exposure to rilpivirine is 40% lower when taken under fasting conditions as compared to a normal
caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When taken with only a protein-rich nutritional drink,
rilpivirine exposures were 50% lower than when taken with a meal.
Hepatic Impairment: No dosage adjustment is necessary with mild to moderate hepatic impairment. The
pharmacokinetics of rilpivirine has not been adequately evaluated in individuals with severe hepatic impairment.
Renal Impairment: No dosage adjustment is necessary for rilpivirine itself patients with mild or moderate renal
impairment. However, in patients with severe renal impairment or end-stage renal disease, rilpivirine should be
used with caution and the fixed-dose combination should not be prescribed for patients with creatinine clearance
below 50 mL per minute, as the tenofovir component requires dose adjustment.
Drug interactions: Do not take with PPI or within 12 hours of H2RA. Drugs that induce CYP3A or inhibit CYP3A may
result in decreased or increased plasma concentrations of rilpivirine. Use caution using with protease inhibitors, azole
antifungals and macrolides – all of which may increase levels of rilpivirine. Rilpivirine does not have an effect on the
exposure of other drugs metabolized by CYP enzymes.
Toxicity: compared with efavirenz, fewer drug discontinuations due to psychiatric disorders & rash (2% vs 4%); overall
decreased abnormal dreams, rash (3% vs 11%), dizziness (1% vs 7%) or increased cholesterol (5% vs 18%)
Supratherapeutic doses of rilpivirine (>75mg) prolong the QTc interval.
Efficacy: Although rilpivirine demonstrated overall non-inferiority vs efavirenz, with viral loads > 100,000 virologic failure
and subsequent resistance occurred more frequently with rilpivirine..
Resistance: RPV-resistance at virologic failure is common and may confer resistance to etravirine
Emergent mutations: V90I, K101E/P/T, E138K/G, V179I/L, Y181I/C, V189I, H221Y, F227C/L and M230L
Mutations a/w ↓activity: K101E/P, E138A/G/R/Q, V179L, Y181C/I/V, H221Y, F227C, M230I/L
PROTEASE INHIBITORS:
Storage and shipping considerations:
Storage Requirements
MAIL
Indinavir (Crixivan)
Room temperature in original container with desiccant packet
Yes
Ritonavir (Norvir)
Capsules- refrigeration recommended but not required if used
No
within 30 days and stored at room temperature (77 F)
Liquid- store at room temperature. Do Not Refrigerate. Shake Yes
with each use
Nelfinavir (Viracept)
Room temperature
Yes
Amprenavir (Agenerase) Room temperature
Yes
Lopinavir/r (Kaletra)
Room temperature
Yes
Atazanavir
Room temperature
Yes
Tipranavir
Yes
Stable for 2 months at room temperature (77 F)
Refrigerated capsules stable until date on label
Darunavir
Room temperature
Yes
PK considerations: Multiple drug-drug interactions. Poor CSF penetration. Avoid St. John’s Wort
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fAPV
IDV
LPVr
NFV
RTV
SQV*
ATV
TPV
Plasma half-life (hr)
7-10.6
1.5-2
5-6
3.5-5
3-5
1-2
6.5
5.5
Protein Binding (%)
90%
60%
98-99%
>98%
9899%
97%
86%
99.9%
Metabolism (substrate)!
3A4
3A4
3A4
3A
3A,2D6
3A4
3A
3A4
p450 inhibitor of
3A4
3A4
3A4,
2D6
3A
3A4,
2D6
3A4
3A,1A1,1
A2,2C9
26D (with
rtv)
*saquinavir soft gel capsules. **ND – not determined
Drug
# Pill per dose
Schedule
Amprenavir
8
BID
!
cytochrome p450 enzyme/isoenzymes
Hepatic Dosing**
Diet restrictions
CP 5-8
+/- food
avoid high fat
Indinavir
2
Q8H
“Mild to Moderate”
empty stomach or light
snack (no fat)
Lopinavir/ritonavir
3
BID
unknown
with food
Nelfinavir
2
BID
unknown
with food
Ritonavir
6
BID
unknown
with food
Saquinavir
2 (1)*
ID
unknown
with food
Atazanavir
2
QD
CP Class B
with food
Tipranavir/rtv
2 (1)*
BID
Contra-indicated in
with food
CP class B & C
Darunavir/rtv
2 (1)*
BID
Unknown
with food
* *100 mg of RTV needs to be taken with each dose of the base protease inhibitor. **Hepatic Dosing – some
products have been studied in patients with hepatic insufficiency. CP refers to Child-Pugh score in number or class.
These agents require some degree of dose reduction. Unknown – no studies have been performed in this
population.
Erectile dysfunction agents:
Sildnafil: All => 2 - 11x  sildenafil AUC; start with 25 mg dose; with RTV do not exceed 25 mg sildenafil over 48
hours).
Vardenafil: do not use with unboosted IDV; start with 2.5 mg dose and do not exceed 2.5 mg in 72 if used with
ritonavir
Tadalafil: start with 5 mg dose and do not exceed a single dose of 10 mg every 72.
Lovastatin and simvastatin: Avoid (extensively metabolized via CYP3A4 , PI or delavirdine inhibition of statin
metabolism may   statin concentration  myositis), pravastatin, atorvastatin (except with DRV[5x  in some
subjects, start with lowest dose] or RTV at doses of 400 mg), cerivastatin or fluvastatin are preferred.
Common contra-indicated drugs:
Cisapride:
Rifampin (may substitute rifabutin in some instances)
Midazolam, triazolam: substitute temazepam or lorazepam.
Astemizole, terfenadine: substitute loratidine, fexofenadine, or cetirizine
Ergot alkaloids
St. John’s wort (decreased absorption)
Beware proton pump inhibitors (decreased absorption for atazanavir per P.I.), indinavir (ICAAC 2003 #A-1611),
See separate PK section for interactions with other NNRTIs, PIs, rifampin, and rifabutin.
Common toxicities:
Drug
Most common side effects*
Fos-amprenavir
nausea, vomiting, diarrhea, rash, oral paresthesias, hyperglycemia, dyslipidemias
indinavir
nephrolithiasis, nausea, hyperbilirubinemia, headache, asthenia, dizziness, rash, metallic
taste, thrombocytopenia, alopecia, hyperglycemia, dyslipidemias
lopinavir/ritonavir
nausea, vomiting, diarrhea, asthenia, elevated transaminases, hyperglycemia, dyslipidemias
nelfinavir
diarrhea, bloating, hyperglycemia, dyslipidemias
ritonavir
nausea, vomiting, diarrhea, paresthesias (circumoral and peripheral), hepatitis, pancreatitis,
asthenia, taste perversion, elevated transaminases, uric acid, CPK, hyperglycemia,
dyslipidemias
saquinavir
nausea, diarrhea, abdominal pain, dyspepsia, headache, elevated transaminases,
hyperglycemia, dyslipidemias
atazanavir
nausea, vomiting, diarrhea, abdominal pain, jaundice/scleral icterus, depression,
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hyperbilirubinemia, rash
Diarrhea, other GI,  LFTs; Contra-indicated in Child Pugh class B & C. Rash 8 – 10%; 
in women; possible cross-reactivity with sulfa agents.  cholesterol, triglycerides
darunavir
nausea, vomiting, diarrhea, pancreatitis, elevated transaminases and alkaline phosphatase,
uric acid, , hyperglycemia, dyslipidemias
Fluticasone and ritonavir: concomitant use of results in significantly  serum cortisol concentrations. Co-administration
of fluticasone and ritonavir or any ritonavir-boosted PI regimen is not recommended unless the potential benefit
outweighs the risk of systemic corticosteroid side effects.
Increased bleeding and factor VIII requirements in hemophiliacs
Osteopenia and Osteoporosis: risk of avascular necrosis, osteopenia and osteoporosis is significantly higher in patients
taking PIs compared with patients taking non-PI containing regimens.
Also: Dry skin and cracked lips, loss of body hair, ingrown toenails, premature coronary artery disease, male
gynecomastia, elevated uric acid and gout
Amprenavir (Agenerase™,APV;). removed from market in 2005 and replaced with fos-amprenavir
Fos-Amprenavir (Lexiva™): prodrug of amprenavir
Dosage: Approved regimens include f-APV 1400 bid, f-APV 700 bid/RTV 100 mg bid, f-APV 1400 qd/RTV 200 mg qd.
RTV boosted bid regimen preferred for salvage patients. May be taken with or without food; do not co-administer with
simultaneous H2RA unless RTV-boosted (but PPI OK). Stable at room temperature.
Pharmacology . Metabolism and drug-drug interactions per amprenavir. No data exists regarding appropriate dosage
with RTV in patients with hepatic insufficiency.
Contraindications: midazolam, triazolam, cisapride, pimozide or ergot alkaloids. Avoid simvastatin, lovastatin.
Toxicity: 5% diarrhea without RTV, 10% diarrhea with RTV; rash. Potential cross-reactivity with sulfonamides. More
dyslipidemia than with ATV/rtv; associated with  MI rate.
Atazanavir (Reyataz™): azapeptide inhibitor of HIV-1 protease. Available in 100, 150 and 200 mg capsules
Dosage: 400 mg (two 200 mg capsules) qd with food (standard), 300/100 mg qd (ATV/RTV)
Pharmacology: light meal  70%  AUC; 86% protein bound (AAG and albumin); No data with renal failure. Reduced
absorption with increased gastric pH.
Drug-drug interactions: extensive hepatic metabolism by CYP3A . Inhibits CYP3A and UGT1A1 (UDP-glucuronosyl
transferase;   irinotecan levels). See drug chart
Effects on ATV: Concomitant EFZ and RTV have balanced effects on ATV levels ( by EFZ vs  by RTV). 
ATV solubility and  absorption if given with proton pump inhibitors (in treatment-experienced patients do
not use with ATV or ATV/rtv; in treatment naïve patients PPI does may not exceed 20 mg dose equivalent of
omeprazole and must be given 12 prior to ATV/rtv 300/100 mg). ), antacids (give at separate times), buffered
ddI tablets (give at separate times), H2 receptor antagonists (separate dosing by 12 hours) or with tenofovir
(use tenofovir only with ATV/RTV 300/100, note that this  30%  [TFV]).
Effects on other drug: ATV  6x  SQV Cmin, 3.5x  RFV Cmin, 2x  diltiazem ( diltiazem dose by 50%, monitor
EKG). No data with verapamil, digoxin and blockers (other than atenolol marginal effect).  amiodarone and
tenofovir levels
Contraindications: midazolam, triazolam, cisapride, ergot alkaloids, pimozide,
Toxicity: minor  PR interval (but avoid in patients with marked 1 or 2/3 heart block ; hyperbilirubinemia (30 – 50% of
pts with total bili > 2.6 x ULN; primarily increase of indirect bili related to UGT1A1 inhibition [genotype-dependent]).
Hepatotoxicity and  bilirubin not affected by HBV/HCV infection.
Darunavir (DRV, Prezista™): biliary excretion and CYP3A4 metabolism
Dosage: 600 mg q 12 hours (300 mg tablets) must be taken with ritonavir 100 mg q 12. Doses should be taken with
food. No dosing change with renal insufficiency; use with caution in patients with significant hepatic impairment.
Drug interactions: CYP 3A4 inhibitor and substrate. 37%  voriconazole with 100 mg bid RTV.  AUC with
ketoconazole,  AUC pravastatin (use fluvastatin), 57%  clarithromycin AUC. DRV[5x]  in some subjects, start
with lowest dose]. Contains sulfonamide moiety. No significant effect on absorption by proton pump inhibitors.
Contraindications: amiodarone, astemizole, cisapride, triazolam midazolam, ergot alkaloids.
Toxicity: potential sulfa cross-reactivity; contains a sulfonamide moiety.
Resistance: correlates with the number of mutations at 10 specific sites (protease codons V11I, V32I, L33F, I47V, I50V,
I54L/M, G73S, L76V, I84V, L89V).
Number of mutations from above list
0-2
3
4
Achievement of VL < 50 @ 24 wks
50%
22%
10%
Little cross resistance with TPV/r, although extensive cross-resistance with other PIs.
Indinavir (IDV; Crixivan™): Biliary excretion, less than 20% excreted unchanged in the urine.
tipranavir
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Dosage: 800 mg q 8 hours (400 mg tablets). 1.5 liters fluid intake per day. Dose 1° before or 2° post meals and at least
1° apart from ddI. May take with dry toast, jelly, apple juice, corn flakes, skim milk, and coffee. Patients with mild to
moderate hepatic insufficiency and clinical evidence of cirrhosis have approximately 60% higher mean AUC.
Drug interactions:  AUC with ketoconazole and itraconazole ( IDV to 600 q8° for both). No significant effect on
ethinyl estradiol or norethindrone. Absorption decreased 50% by proton pump inhibitor use.
Contraindications: amiodarone, astemizole, cisapride, triazolam midazolam, rifampin, ergot alkaloids.
Toxicity: nephrolithiasis (4%), nausea, vomiting, asymptomatic hyperbilirubinemia (10%), headache, dizziness, 
platelets, metallic taste. Avoid in late-term pregnancy (neonatal kidney stones,  bili). Possible increased risk of
DVT/pulmonary embolism.
Lopinavir (Kaletra™, formerly ABT-378). Stable for 2 months at room temperature.
Dosage: 400/100 (400 mg LPV + 100 mg RTV in co-formulated 200/50 mg tablets) bid  trough [LPV] 50x EC50 of wtHIV; may also be given as 800/200 qd (four 200/50 mg co-formulated tablets) in treatment naïve individuals; may  to
600/150 mg when given to patients with suspected  susceptibility; QD dosing is approved only for treatment naïve
patients and is associated with increased diarrhea.
Pharmacology: tablet formulation can be taken with or without food and does not require refrigeration.  dose to
600/150 (3 tablets) when given with EFZ or NVP (both  LPV by ~ 30%). 98% protein-bound. LPV metabolized by
CYP3A4 (blocked by RTV). Negligible renal clearance.
Drug-drug interactions: See list of drug-drug considerations for ritonavir. Contraindications: flecainide, propafenone,
terfenadine, astemizole, midazolam, triazolam, cisapride or ergot alkaloids, pimozide, rifampin. Carefully monitor with
amiodarone, bepridil, systemic lidocaine, tricyclic anti-depressants, quinidine, hormonal contraceptives, warfarin. LPV
  ketoconazole, itraconazole, tenofovir. LPV  by carbamazepine, phenobarbital, phenytoin. 53%  methadone
AUC.
Toxicity (with RTV): loose stools, asthenia, headache, abdominal pain, rash, hepatitis,  chol/TG. More dyslipidemia
than with ATV/rtv; associated with  MI rate.
Resistance: correlates with the number of mutations at 11 specific sites (protease codons 10, 20, 24, 46, 53, 54, 63, 71,
82, 84, and 90).
Number of mutations
0-3
4-5
6-7
8-10
Fold-increase in EC50
0.8
2.7
13.5
44.0
Achievement of VL < 400
24/25 (96%)
16/21 (76%) 2/6 (33%)
Nelfinavir (NFV; Viracept™): 78% biliary excretion.
Dose: two 625 mg tablets q 12 hours with food ( 2-3X  AUC). Ketoconazole  NFV AUC. NFV   ethinyl estradiol
and norethindrone AUC (use other contraception).
Contraindications: Pregnancy. terfenadine, astemizole, cisapride, triazolam, midazolam, ergot alkaloids. 2 - 11x 
sildenafil AUC (do not exceed 25 mg sildenafil over 48 hours). Avoid simvastatin, lovastatin.
Toxicity: Diarrhea
Ritonavir (RTV; Norvir™): biliary excretion.
Dosage: Rarely used as monotherapy (600 mg bid; six 100 mg capsules) due to toxicities. Better tolerated with meals,
absorption  by ddI. Initiate dosage at 300 mg bid then increase gradually to full dose over 7 - 14 days. Formulation
of capsules includes alcohol. Keep capsules refrigerated! Do not refrigerate oral solution
Drug interactions: RTV AUC  by phenobarbital, carbamazepine, dexamethasone, and phenytoin. RTV  77% 
clarithromycin AUC ( clarithromycin dose by 50 - 75% in patients with  CrCl), 400%  rifabutin ( dose to 150 mg
qod), 300%  ketoconazole (max dose 200 mg qd), and 145%  desipramine (reduce dose). 40 – 80% 
voriconazole AUC with 100 – 400 mg RTV bid; RTV  40%  ethinyl estradiol AUC, 43%  theophylline (increase
dose), and substantial decrease in methadone levels. Note: 100 – 200 mg of RTV bid does not prevent induction of
CYP3A4 activity by rifampin.
Contra-indicated drugs
Potential Alternatives
Generic Name
Brand Name
Generic Name
Brand Name
Meperidine
Demerol
Oxycodone
Percodan
Piroxicam
Feldene
lbuprofen
Motrin
Propoxyphene
Darvon
Acetaminophen
Tylenol
Bupropion
Wellbutrin
Fluoxetine
Prozac
Alprazolam
Xanax
Temazepam
Restoril
Diazepam
Valium
Lorazepam
Ativan
Flurazepam
Dalmane
Triazolam
Halcion
Zolpidem
Ambien
Amiodarone
Cordarone
Very limited clinical experience
Bepridil
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Encainide
Enkaid
Flecainide
Tambacor
Propafenone
Rythmol
Quinidine
Clozapine
Clorazil
Very limited clinical experience
Primozide
Other contra-indicated drugs: bepridil, cisapride, clorazepate, estazolam, midazolam, ergot alkaloids, disulfiram
(RTV capsules and solutions contain ethanol).
Toxicity: Increased triglycerides, AST/ALT, GGT, CPK, uric acid. Asthenia, nausea, vomiting, diarrhea, altered taste,
paresthesias; nausea may be reduced by initial dose escalation over several days.
Saquinavir (SQV; hard-gel capsule = Invirase™ (200 mg and 500 mg capsules); biliary excretion. 90%
metabolized by CYP3A4; < 1% urinary excretion. Refrigerate or store at room temperature (up to 3 months).
Fortovase™ preparation no longer distributed in the United States as of February 2006.
Dosage: Invirase™; recommended dose = 1000/100 mg (bid of SQV/RTV. Must be used with ritonavir.
Drug interactions: 90% metabolized by CYP3A4; < 1% urinary excretion. Phenobarbital, phenytoin, dexamethasone,
carbamazepine =>  SQV AUC. Ketoconazole  3X  SQV AUC. SQV  3x  sildenafil AUC.
Contraindications: terfenadine, astemizole, midazolam, cisapride or ergot alkaloids.
Toxicity: diarrhea, nausea; occasional abdominal pain, headache, abnormal transaminases.
QT prolongation: SQV/rtv may cause  QT interval; avoid in patients with taking medications known to cause QT
interval prolongation such as Class IA (such as quinidine,) or Class III (such as amiodarone) antiarrhythmic
drugs, or in patients with a history of QT interval prolongation. An electrocardiogram (EKG) should be
performed prior to initiation of treatment. In addition, consider whether ongoing EKG monitoring is appropriate
for your patient and when it should be done. Patients with a QT interval > 450 msec should not receive ritonavirboosted Invirase. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after
approximately 3 to 4 days of therapy.
Tipranavir (Aptivus®; TPV)
Structure: Uniquely, non-peptidic PI.
Dosage: TPV/RTV = 500/200 bid; 250 mg TPV capsule. Substrate of CYP3A. Ritonavir increases trough levels by 7- to
40-fold. Take with food. Hepatic metabolism. Must be used with ritonavir.
Drug-drug interactions:  [ddI], take ddI and TPV at 2 hour intervals.  itraconazole and ketoconazole concentration
(max dose = 200 mg qd with both); fluconazole   TPV (max fluconazole dose 200 mg qd). Cr Cl 30 – 60: 
clarithromycin 50%; Cr Cl <30:  clarithromycin 75%. TPV/rtv inhibitis CYP 26D; expect P-gp induction. 30% 
[TPV] if given with simultaneous antaacid See list of drugs contra-indicated with ritonavir.
Activity: Active against IDV and RTV-resistant isolates? 48V and 82A => "hypersensitivity", 48V, 82A, and 90M =>
sensitivity.
Resistance mutations: Resistance via L33I/F/V, 82T, 84V and 90M; best activity if < 3 such mutations. Other data
are shown below.
Selected mutations: TPV/rtv most commonly selects for L33F, V82L, I84V; other selected mutations include
L10V/I/S, I13V, E35D/G/N, I47V, K55R, V82L and L89V/M
Mutations associated with decreased TPV/rtv response: Presence of 5 or more of the following PI mutations
associated with decreased virological response: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L,
I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V.
Toxicity: Diarrhea, other GI,  LFTs; Contra-indicated in Child Pugh class B & C. Rash 2 – 10% ; more common in
women; possible cross-reactivity with sulfa agents.  cholesterol, triglycerides. Formulated with alcohol; avoid
use of disulfiram and metronidazole. 14 intracranial hemorrhage events among 13 of 6,840 HIV-1 infected persons
receiving TPV.
FUSION INHIBITORS
Enfuvirtide (Fuzeon™, T-20)
Structure: 36-amino acid synthetic peptide
Mechanism: binds to the region of HIV-1 envelope GP41 that is involved in mediated viral fusion with CD4+ cell
membrane. Acts after viral binding to CD4+ molecule and either CCR5 or CXCR4.
Dosage: 90 mg sc q 12 hours. No PK interaction with any known agent
Activity: No cross-reactivity with resistance to NRTIs, NNRTIs or PIs. Optimal effect requires combination with at least
two other active agents.
Toxicity/Side Effects:
Injection site reactions (>95%, 3% discontinue w/I 24 wks due to ISRs). 17% of ISRs last more than 7 days.
Other:  rate pneumonia with T-20 (4.7/100 p-y vs 0.6/100 p-y in controls) Trend towards  neuropathy, anorexia,
eosinophilia with T-20.
CCR5 INHIBITORS
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Maraviroc (Selzentry™, MVC)
Mechanism: Binds to CCR5. Acts as allosteric inhibitor of.GP120 binding to CCR5 – does not directly interact with
GP120 binding site on CCR5. Antagonized binding of endogenous CR% ligands.
Pharmacokinetics: metabolized by the liver; renal clearance accounts for ~25% of total clearance.
Dosage:
Concomitant Medications
Maraviroc dosage regimen
CYP3A inhibitors (with or without CYP3A inducers)
150mg orally twice daily
 Protease inhibitors (except tipranavir/ritonavir)
 Delavirdine
 Ketoconazole, itraconazole, clarithromycin, telithromycin
 Other strong CYP3A inhibitors (e.g., nefazadone)
Other concomitant medications including
300mg orally twice daily
 Tipranavir/ritonavir
 NRTIs,
 Nevirapine
 Enfuvirtide
 Drugs that are not strong CYP3A inhibitors or inducers
CYP3A inducers (without a strong CYP3A inhibitor) including
600mg orally twice daily
 Efavirenz
 Rifampin
 Carbamazepine, phenobarbital, phenytoin
Hepatic Impairment: Pharmacokinetics have not been adequately evaluated in individuals with hepatic impairment.
Renal Impairment: Pharmacokinetics have not been adequately evaluated in individuals with renal impairment.
Patients with a with creatinine clearance of less than 50 mL/min may experience dose-related adverse events
such as dizziness and postural hypotension.
Activity: Active only against R5-tropic virus. Tropism test must be done before use. Patients with dual/mixed tropic virus
or pure X4 virus do not have virological responses to MVC. Virologic failure is due to both emergence of X4-tropic
subpopulations or to mutations in GP120 which allow virus to utilize CCR5 which has bound MVC (“Virus learns to
learn the drug”). No cross-reactivity with resistance to NRTIs, NNRTIs or PIs. Optimal effect requires combination
with at least two other active agents.
Toxicity/Side Effects: The most common treatment related adverse events occurring in >5% of patients treated with
maraviroc were diarrhea, nausea, headache, pyrexia, and fatigue and were similar in the placebo group. Other
noteworthy adverse events reported in >2% of MVC recipients and exceeding the rate in the placebo group by 3% or
3-fold, include URI, cough, dyspnea,  CPK, rash, HSV infection, increased AST/ALT, myalgia. Rare hepatic
hypersensitivity reactions.
INTEGRASE INHIBITORS
Raltegravir (Isentress, RAL)
Mechanism: HIV-1 integrase strand transfer inhibitor; prevents integrative of reverse transcribed HIV RNA (HIV proviral
DNA) into host chromosome). Reaction requires three steps: 1) assembly of a stable preintegration complex at the
termini of the viral DNA; 2) 3’-end endonucleolytic processing to remove the terminal dinucleotide from each 3’ end of
viral DNA; 3) strand transfer in which the viral DNA 3” ends are covalently linked to the cellular DNA.
Pharmacokinetics: metabolized by glucoronidation mediated by uridine diphosphate glucuronosyl transferase 1A1
isozyme (UGT1A1). RAL is not an inhibitor, inducer, or substrate of the major CYP450 isoenzymes. Highly variable
serum levels appear related to food (19% increase in AUC and 8.5-fold increase in C12hr when administered with
high-fat meal), pH dependent solubility (solubility increases with increasing pH), UGTIA1 polymorphism, UGT1A1
expression (hepatic UGT1A1 protein expression levels vary >50-fold in human liver samples), P-gp expression (high
variability in intestinal P-gp expression levels) or drug-drug interactions (raltegravir is a substrate of UGT1A1 or P-gp).
No dosage adjustment is necessary for patients with renal impairment or mild to moderate hepatic impairment.
Dosage: One 400 mg table twice daily without regard to food. Caution should be used when co-administering RAL with
strong inducers of UGT1A1 (e.g., rifampin, phenytoin, phenobarbital) due to reduced plasma concentrations of RAL.
Resistance: Virologic failure appears to be associated with 2 major pathways, Q148 and N155, which are independently
involved in the emergence of raltegravir resistance. The N155H substitution was the most frequent (40.7%) and
conferred 13.2-fold resistance to raltegravir. The Q148K substitution is a primary contributor to resistance to
raltegravir, conferring a 46-fold reduced susceptibility in cell culture. The G140A/S substitutions play a secondary role
in raltegravir resistance, conferring a 3-fold reduced susceptibility alone. Sequential addition of this substitutions
increased resistance to 521-fold.
Toxicity/Side Effects: rash, elevated ALT/AST, and elevated CPK.
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Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic Infections. N Engl J Med. 2001;
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America. Clin Infect Dis. 2009; 49:651–81.
Gupta SK, Eustace JA, Winston JA, et al. Guidelines for the management of chronic kidney disease in HIV-infected
patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect
Dis. 2005; 40:1559-85.
www.hivguidelines.org This website, which is maintained by the New York State Department of Health AIDS Institute,
provides a number of comprehensive monographs regarding the management of HIV-infection in adults, the sections
on Side Effects of Antiretroviral Therapy and HIV Drug-Drug Interactions are particularly noteworthy.
http://www.aidsinfo.nih.gov/. The AIDS Information Service (AIDS Info) is a Federally sponsored website that
includes the most recent U.S. Department of Health and Human Services guidelines for the management of HIVinfected individuals in the United States.
Qaseem A, Snow V, Shekelle P, Hopkins R, Jr., Owens DK. Screening for HIV in health care settings: a guidance
statement from the American College of Physicians and HIV Medicine Association. Ann Intern Med. 2009;150:12531.
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