Download Guidelines for the Use of Antiretroviral Agents in Adults

Special Issues
Guidelines for the Use of
Antiretroviral Agents in
Adults and Adolescents
published October 2006
AETC NRC Slide Set
About this Presentation
These slides were developed using the October 2006 Treatment
Guidelines and the April 2007 Supplement to the Guidelines.
The intended audience is clinicians involved in the care of
patients with HIV.
The user is cautioned that due to the rapidly changing field of
HIV care, this information could become out of date quickly.
Finally, it is intended that these slides be used as prepared,
without changes in either content or attribution. Users are asked
to honor this intent.
-AETC NRC
http://www.aidsetc.org
10/06
Special Issues: Contents
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Acute HIV infection
Treatment for Adolescents
Treatment for Pregnant Women
Injection Drug Users
Patients with Hepatitis B or C Co-Infection
Mycobacterium Tuberculosis
Prevention Counseling
10/06
Acute Retroviral Syndrome:
Signs and Symptoms - I
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Fever
Lymphadenopathy
Pharyngitis
Rash
Myalgia or arthralgia
Diarrhea
96%
74%
70%
70%
54%
32%
10/06
Acute Retroviral Syndrome:
Signs and Symptoms - II
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Headache
Nausea and Vomiting
Hepatosplenomegaly
Weight Loss
Thrush
Neurological Symptoms
32%
27%
14%
13%
12%
12%
10/06
Acute Retroviral Syndrome:
Rash
 Erythematous maculopapular with lesions on the
face and trunk and sometimes extremities
(including palms and soles)
 Mucocutaneous ulceration involving mouth,
esophagus, or genitals (distinguishes HIV from
mononucleosis (EBV)
10/06
Acute Retroviral Syndrome:
Neurological Symptoms
 Meningoencephalitis or aseptic meningitis
(uncommon)
 Peripheral neuropathy or radiculopathy
 Facial palsy
 Guillain-Barré syndrome
 Brachial neuritis
 Cognitive impairment or psychosis
10/06
Acute HIV Infection:
Laboratory Testing
 Detectable HIV RNA with negative or
indeterminate HIV antibody test
 Low-positive HIV RNA (<10,000
copies/mL) may be false positive
 If diagnosis is made by HIV RNA testing,
confirmatory serologic testing should be
performed subsequently
10/06
Acute HIV Infection: Treatment
 Limited outcome data from clinical trials;
therapy based largely on theoretic
considerations
10/06
Acute HIV Infection: Treatment
Possible benefits:
Possible risks:
 Decrease the severity of
acute disease
 Alter the viral “set point”
 Reduce the rate of
mutation
 Preserve immune
function
 Reduce risk of viral
transmission
 Drug-related toxicity
 Earlier emergence of
drug resistance
 Limitation of future
treatment options
 Potential need for
indefinite treatment
 Adverse effects on quality
of life
10/06
Primary Treatment Regimen
 Same as for chronic infection
10/06
The HIV Infected Adolescent
 Timing of infection; perinatal vs.
acquired during adolescence
 Early intervention
10/06
The HIV Infected Adolescent
 Drug pharmacology in puberty
 Dosing based on Tanner stages
 Use adult dosing schedules for those in
late puberty
 For females, address gynecologic care,
contraception (including interactions
with ARV); avoid efavirenz
 Adherence concerns
10/06
The HIV Infected Adolescent
Challenges to adherence:
 Denial and fear of HIV infection; misinformation
 Distrust of the medical establishment;
 Fear and lack of belief in the effectiveness of
medications
 Low self-esteem
 Unstructured and chaotic lifestyles
 Lack of familial and social support
10/06
Treatment for Pregnant Women*
To reduce risk of perinatal transmission:
 Antiretroviral (ARV) therapy recommended
in all pregnant women
 Reduction of HIV viral load to <1000
copies/mL
* See also the US Public Health Services Task Force
“Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1Infected Women for Maternal Health and Interventions to Reduce
Perinatal HIV-1 Transmission in the United States.”
10/06
Treatment for Pregnant Women
 In women not already on ARVs, consider
delaying treatment until 10-12 weeks gestation
 In women already on ARVs, consider continuing
therapy, though effects of ARVs on fetus in first
trimester are uncertain
 Perform resistance testing before starting ARV
therapy or prophylaxis, and in women on ARV
therapy with detectable HIV RNA
10/06
Treatment for Pregnant Women
Regimen considerations:
 Potential pharmacokinetic changes caused by
pregnancy, different dosing requirements
 Potential adverse effects of antiretroviral drugs
on pregnant women
 Effect on the risk for perinatal HIV transmission
 Potential short- and long-term ARV effects on
the fetus and newborn
10/06
Treatment for Pregnant Women
 Include zidovudine, if possible, in ARV regimen
 Recommend 3-part zidovudine prophylaxis
regimen to reduce perinatal transmission
for all pregnant women with HIV infection,
regardless of viral load
10/06
Safety and Toxicity of ART in
Pregnant Women: NRTIs
 Clinical trial data in human pregnancy available
for AZT, lamivudine, didanosine, stavudine
 Mitochondrial toxicity possible with all NRTIs
 Increased risk of lactic acidosis/hepatic steatosis
with didanosine + stavudine*
* This combination should be used only if no other alternatives are available.
10/06
Antiretroviral Drug Use in
Pregnant Women: NRTIs
Recommended Zidovudine
agents
Lamivudine
Efficacy studies and
extensive experience
Should be included in the
regimen unless significant
toxicity or other
contraindication
Zidovudine + lamivudine is
the recommended dual NRTI
backbone
10/06
Antiretroviral Drug Use in
Pregnant Women: NRTIs
Alternate
agents
Didanosine
Emtricitabine
Stavudine
Abacavir
Cases of lactic acidosis with
didanosine + stavudine; use
only if no other alternatives
Insufficient
data to
recommend
Tenofovir
No studies in human
pregnancy; bone toxicity in
monkey studies and some
pediatric studies
Not
recommended
Zalcitabine
Teratogenic in animals
10/06
Safety and Toxicity of ART in
Pregnant Women: NNRTIs
 Clinical trial and pharmacokinetic (PK) data in
human pregnancy available only for
nevirapine
10/06
Antiretroviral Drug Use in
Pregnant Women: NNRTIs
Recommended
agent
Nevirapine No evidence of teratogenicity
Increased risk of liver toxicity in
women who start nevirapine with
CD4>250; in these women, use
nevirapine-based regimens only
if benefit outweighs risk
Not
recommended
Efavirenz
FDA pregnancy category D
Teratogenic in monkeys
Avoid in first trimester; consider
after second trimester only if no
other alternatives
Delavirdine
Teratogenic in rodent studies
10/06
Safety and Toxicity of ART in
Pregnant Women: PIs
 PK and clinical trial data available for nelfinavir,
saquinavir (soft gel capsules)/ritonavir
 Limited data for indinavir, ritonavir, saquinavir hard gel
capsules, and lopinavir/ritonavir (capsules)
 PK and clinical studies on indinavir/ritonavir and
lopinavir/ritonavir are underway
 Other PIs not yet studied
 Concern for increased risk of hyperglycemia:
monitor closely
 Conflicting data re: preterm delivery in women
receiving PIs
10/06
ART in Pregnant Women: PIs
Recommended Lopinavir/
agents
ritonavir
Nelfinavir
Dosing recommendations not
established; may require
increased dose during pregnancy
No PK data on tablet formulation
Limited clinical experience; study
underway
PK data and extensive clinical
experience in pregnancy
Preferred PI for use in pregnant
women
10/06
Antiretroviral Drug Use in
Pregnant Women: PIs
Alternate Indinavir
agents
Lower drug levels during pregnancy
Must boost with ritonavir, but optimal dosing
in pregnancy is unknown
Concern for possible hyperbilirubinemia in
the neonate
Ritonavir
Lower drug levels in pregnancy
May use at low dose as booster for other PIs
Saquinavir
(hard gel
capsule)/
ritonavir
Must boost with ritonavir
PK studies and moderate experience with
soft gel capsules; limited data on hard gel
capsule
No PK data on tablet formulation
10/06
ART in Pregnant Women: PIs
Insufficient
data to
recommend
Amprenavir
No studies in human pregnancy
Oral solution contraindicated
(contains propylene glycol)
Atazanavir
No studies in human pregnancy
Concern for possible
hyperbilirubinemia in the neonate
Darunavir
No studies in human pregnancy
Fosamprenavir
No studies in human pregnancy
Tipranavir
No studies in human pregnancy
10/06
Antiretroviral Drug Use in
Pregnant Women: Fusion
Inhibitors
Insufficient
data to
recommend
Enfuvirtide
No studies in human pregnancy
10/06
Injection Drug Users
 Transmission via injection drug use is
second most common transmission route
in the U.S.
 Injection drug users (IDU)
 Often have multiple comorbidities,
 Increased morbidity and mortality,
 Decreased access to HIV care
 Are less likely to receive ARV
10/06
Injection Drug Users
Efficacy of HIV treatment
 In IDU who are not actively using, efficacy
similar to other populations
 Active drug use may interfere with adherence
and ARV success
 In some patients, substance abuse treatment
may be required for ARV success
 Many other support mechanisms may be
effective
10/06
Injection Drug Users
Drug toxicities and interactions
 IDU may have more ARV-related adverse effects
 Methadone may interact significantly with ARV
 NRTI: no significant effects on methadone levels; AZT
levels increased
 NNRTI: EFV and NVP decrease methadone levels
 PI: APV, NFV, LPV decrease methadone levels;
methadone decreases APV levels
 Buprenorphine: limited data on interactions with
ARVs
10/06
HBV/HIV Co-Infection:
ARV considerations
 Unclear if HBV treatment improves the course of
HIV infection
 Unclear if HIV treatment alters the course of
HBV
 In HBV/HIV patients, liver toxicity from ARVs
and flares of HBV may complicate HIV treatment
10/06
HBV/HIV Co-Infection:
ARV considerations
 Emtricitabine, lamivudine, and tenofovir have
activity against both HIV and HBV
 Discontinuation may cause HBV flares
 Case reports suggest entecavir may have
activity against HIV as well as HBV
 HBV resistance to lamivudine monotherapy
 40% at 2 years
 90% at 4 years
10/06
HBV/HIV Co-Infection:
ARV considerations
 Immune reconstitution may result in LFT
deterioration
 Patients with immune reconstitution may have loss of
e antigen (HBeAg), associated with HBV flare
 All PIs and NNRTIs may increase transaminase
levels; ARV toxicity may be difficult to distinguish
from HBV flare (and possible precursor to
HBeAg seroconversion)
10/06
HBV/HIV Co-Infection: Treatment
Recommendations
For all HBV/HIV co-infected patients:
 Counsel avoidance of alcohol
 Vaccinate against hepatitis A (if not immune)
 Advise on methods to prevent HBV
transmission
 Evaluated extent of HBV infection
10/06
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to treat HIV, not HBV:
 Consider the combination of tenofovir +
emtricitabine or lamivudine as NRTI backbone
of ART
 Avoid using these as single drugs with antiHBV activity, to avoid HBV resistance
10/06
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to treat both HIV and HBV:
 Tenofovir + emtricitabine or tenofovir +
lamivudine are first-choice NRTI backbones
 Consider entecavir for HBV treatment, with or
without one of these NRTIs
 Avoid using the NRTIs as single drugs with
anti-HBV activity, to avoid HBV resistance
10/06
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to treat HBV, not HIV (1):
 To avoid drug resistance to HIV, consider
 Pegylated interferon-alpha (no anti-HIV activity)
 Adefovir (no anti-HIV activity at doses used for
HBV treatment; theoretic risk for development of
HIV resistance)
 Avoid emtricitabine, lamivudine, and tenofovir
except as components of fully-suppressive ART,
unless preexisting HIV resistance
10/06
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to treat HBV, not HIV (2):
 Entecavir no longer recommended in patients
not on suppressive ART
 Case reports suggest entecavir may be active
against HIV; the risk of developing HIV resistance
cannot be excluded
10/06
HBV/HIV Co-Infection:
Treatment Scenarios
 Need to discontinue emtricitabine,
lamivudine, or tenofovir:
 Flares of HBV possible; monitor closely
 Consider adefovir or entecavir* to prevent
flares, especially if hepatic reserve is marginal
* Do not use without concomitant suppressive ART
10/06
HCV/HIV Co-Infection
 Higher rates of progressive liver disease in HIV/
Hepatitis C (HCV co-infection
 Unclear if HCV increases HIV progression
 Poor prognosis; unclear if HIV treatment
improves morbidity and mortality for untreated
HCV
 Higher rates of ARV-associated hepatotoxicity
10/06
HCV/HIV Co-Infection
Treatment indicated:
 Detectable plasma HCV RNA and bridging or
portal fibrosis on liver biopsy
 Consider other factors such as:
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stage and stability of HIV disease
other co-morbidities
probability of adherence
possible contraindications to HCV medications
10/06
HCV/HIV Co-Infection: Treatment
Pegylated interferon + ribavirin for 48 weeks
 Low rates of sustained virologic response
in genotype 1
 Limited data on patients with CD4 <200
cells/mm³
10/06
HCV/HIV Co-Infection: Treatment
Potential for drug-drug interactions and additional
toxicity in HIV/HCV:
 Avoid use of DDI with ribavirin (neuropathy,
pancreatitis, lactic acidosis)
 Avoid use of AZT with ribavirin, if possible
(anemia)
 Monitor closely for hepatotoxicity due to ARV
 Monitor closely for neutropenia (due to
interferon) and anemia (due to ribavirin);
hematopoetic growth factors
10/06
TB/HIV Co-Infection
 Increased risk of progression from latent
to active TB
 Increased risk of HIV progression
10/06
TB/HIV Co-Infection:
Treatment Considerations
 The treatment of TB in patients with HIV
infection should follow the same principles for
persons without HIV infection
 For active TB, initiate treatment immediately
 Directly observed therapy is strongly
recommended
10/06
TB/HIV Co-Infection:
Treatment Considerations
 In patients on ARV therapy, evaluate ARV
regimen for interactions with TB drugs
 In ARV-naive patients, avoid simultaneous
initiation of treatment for TB and HIV
 consider delay of ARVs for 4-8 weeks after
initiation of TB treatment to avoid overlapping
of adverse reactions and paradoxical
reactions
10/06
TB/HIV Co-Infection:
Treatment Considerations
 Rifampin/rifabutin-based regimens should be
given at least three times weekly in patients with
CD4+ T cell count <100 cells/mm3
 Once weekly rifapentine is not recommended in
HIV-infected patients
10/06
TB/HIV Co-Infection:
Treatment Considerations
 Rifamycin should be included in TB regimens
 Potential drug-drug interactions with PIs and NNRTIs
 Rifampin may be used only with efavirenz or full-dose
ritonavir
 Rifampin may not be used with ritonavir-boosted PIs
 Rifabutin recommended with nevirapine, other PIs
 Dosage adjustment may be necessary
10/06
TB/HIV Co-Infection:
Treatment Considerations
 Paradoxical reactions more common with
immune reconstitution due to ARV
 Continue treatment for tuberculosis and
HIV, use non-steroidal anti-inflammatory
agents
 In severe cases consider use of highdose prednisone
10/06
Prevention Counseling in the
Patient with HIV Infection
 Recent increases in HIV seroprevalence
in some populations, especially MSM
 Associated increase in sexually
transmitted infections (STI) and unsafe
sex practices
10/06
Prevention Counseling in the
Patient with HIV Infection
An essential component of HIV patient care:
 Reinforce prevention messages at each
encounter
 Assess patient’s understanding of HIV
transmission
 Assess patient’s HIV transmission behaviors
 Discuss strategies to prevent transmission
(individualize)
10/06
Prevention Counseling in the
Patient with HIV Infection
Sexual transmission
 Decreased with low plasma VL (though
inconsistent relationship between plasma
and genital fluid VL)
 Increased with: concurrent STI, genital
irritation (incl. nonoxynol-9), menstruation,
OCP use, non-circumcision in men
10/06
Prevention Counseling in the
Patient with HIV Infection
Emphasize:
 Importance of barrier protections, “safer”
sex practices, ARV adherence
 For women:
 pregnancy prevention counseling in those
who wish to avoid pregnancy
 preconception counseling in those who wish
to become pregnant
10/06
Web Sites to Access the
Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
10/06
About this Slide Set
 This presentation was prepared by Susa
Coffey, MD for the AETC National
Resource Center in October 2006 and
revised in April 2007.
 See the AETC NRC Web Site for the
most current version of this presentation.
http://www.aidsetc.org
10/06