Antiretroviral Treatment of Adult with HIV Infection The guidelines of International Antiviral Society - USA Panel

Antiretroviral Treatment of Adult with HIV Infection The guidelines of International Antiviral Society - USA Panel Presented by : Dr Hythum Salah Hassan –MBBS-AAHIVS.

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IM-Infectious Diseases Division

March 2014

Brain storm

Which statement about initiating Anti Retroviral therapy (ART) according to (WHO) and International Antiviral Society - USA Panel recommendation is most TRUE?

A. Treat if CD4 count is <200.

B. consider treatment if CD4 count is <350 and initiate ART before CD4 count falls below 200.

C. Treat irrespective of CD4 count.

D. Do not treat till CD4 count is < 100.

E-Treat if CD4 count is < 500 .

Presented by : Dr Hythum Salah Hassan –MBBS-AAHIVS.

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Which statement about initiating drug therapy (ART) according to (WHO) and International Antiviral Society - USA Panel recommendation is TRUE?

A. Treat if CD4 count is <200.

B. consider treatment if CD4 count is <350 and initiate ART before CD4 count falls below 200.

C. Treat irrespective of CD4 count.

D. Do not treat till CD4 count is < 100.

E-Treat if CD4 count is < 500 .


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40 years old male , diagnosed 3 years ago with HIV , he was doing well with CD4 count 725 copies/ml at the time of diagnoses , he missed follow up with HIV Specialist , now he came with feeling of fatigue and generally unwell , CD4 count is 455 copies/ml , Viral load is 11800 copies /ml , other investigations all are normal , you decided to start ART after disused and agreed by patient , what will be the initial regimen of ART ?

A-Darunavir plus abacavir/lamivudine

B-Lopinavir/r plus tenofovir

C- tenofovir/emtricitabine

D-Efavirenz/tenofovir/emtricitabine

E- Efavirenz plus Darunavir/r.


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A-Darunavir/r plus abacavir/lamivudine

B-Lopinavir/r plus tenofovir

C- tenofovir/emtricitabine

D-Efavirenz/tenofovir/emtricitabine (AIa) .

E- Efavirenz plus Darunavir/r.


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Classify the following Antiretroviral Agent by its action: efavirenz

A.Nucleoside reverse transcriptase inhibitors

B.Non-nucleoside reverse transcriptase inhibitors

C.Protease Inhibitors

D- Integrase Inhibitor


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Classify the following Antiretroviral Agent by its action: efavirenz

A.Nucleoside analog reverse transcriptase inhibitors

B.Non-nucleoside reverse transcriptase inhibitors

C.Protease Inhibitors

D- Integrase Inhibitor


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Recommendation and Rationale

MAIN RECOMMENDATION

The New recommendations for HIV patient care include offering ART to all patients regardless of CD4 cell count .

Rationale Patients starting ART when CD4 counts are < 350/μL have greater morbidity and mortality

than those starting when CD4 counts are < 500/μL

Increasing evidence of detrimental effects of uncontrolled viremia at CD4 cell counts > 500/µL

Uncontrolled HIV replication, immune activation and inflammation associated with increase risk of ‘non-AIDS’ illnesses like Cardiovascular, hepatic, renal diseases and malignancies and ART with high CD4 associated with decreased incidence of diseases .

Thompson et al, JAMA, 2012


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In the HIV-CAUSAL collaboration Study , there was a significant and steady decrease in AIDS-free survival as the CD4 cell count threshold for initiation of therapy decreased .

There was an estimated 38% increase in the hazard of AIDS or death when therapy was initiated below a CD4 cell count of 350/µL compared with 500/µl.

The COHERE study of 75 336 individuals examined the prognostic value of the CD4 cell count after virologic suppression by ART and noted that higher CD4 cell count was associated with incremental decreases in the risk of new AIDS events, all-cause mortality, and non AIDS mortality .

Thompson MA, Aberg JA. Antiretroviral Treatment of Adult HIV Infection 2012 Recommendations of the International Antiviral Society–USA Panel. The Journal of American Medical Assocation. 2012.;308(4) .


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What is the Benefits from Early Start ART .

Prevention of progressive immune dysfunction (reduced immune activation)

Delayed progression to AIDS and prolonged survival

Decreased risk of non-AIDS/HIV-related morbidity (HIVAN, malignancies, neurocognitive dysfunction, cardiovascular disease, etc)

Decreased drug resistance

Decreased risk for some ARV toxicities

Decreased HIV transmission



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What is the Risk from Early Start ART

Reduced quality of life

Development of drug resistance if adherence is suboptimal

Limitation in future choices of ART if drug resistance occurs

Uncertain long-term toxicities and duration of effectiveness for some drugs/regimens

Possible transmitted drug resistance



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Strength and quality of evidence are highest with

CD4 count < 500 cells/µL

Pregnancy

HBV or HCV co infection

HIV-associated nephropathy

Active or high risk for cardiovascular disease

Opportunistic infections, including tuberculosis and meningitis

Age older than 60 years

Primary HIV infection

High risk for HIV transmissionThompson et al, JAMA, 2012.

CD4 < 500 cells/µL (AIa)

CD4 > 500 cells/µL (BIII)

Pregnancy (AIa)

Chronic HBV (AIIa)

HCV (may delay until after HCV treatment if CD4 > 500) (CIII)

Age older than 60 (BIIa)

HIV-associated nephropathy (AIIa)

Acute phase of primary HIV infection, regardless of symptoms (BIII).


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Summary of New WHO Recommendations June 2013

As a priority, ART should be initiated in all individuals with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and individuals with CD4 count ≤350 cells/mm3 .

ART should be initiated in all individuals with HIV with CD4 count >350 cells/mmsup>3 and ≤ 500 cells/mmsup>3 regardless of WHO clinical stage .

ART should be initiated in all individuals with HIV regardless of WHO clinical stage or CD4 cell count in the following situations:

1- Individuals with HIV and active TB disease .

2- Individuals coinfected with HIV and HBV with evidence of severe chronic liver disease .

3- Partners with HIV in serodiscordant couples should be offered ART to reduce HIV transmission to uninfected partners .


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All pregnant and breastfeeding women with HIV should initiate triple ARVs (ART), which should be maintained at least for the duration of mother-to-child transmission risk.

First-line ART should consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse-transcriptase inhibitor (NNRTI).

TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART .

If TDF + 3TC (or FTC) + EFV is contraindicated or not available, one of the following options is recommended:

1-AZT + 3TC + EFV

2- AZT + 3TC + NVP

3- TDF + 3TC (or FTC)

Consolidated ARV guidelines, June 2013.

WHO, HIV/AIDS.2013http://www.who.int/hiv/pub/guidelines/arv2013/intro/rag/en/index4.html.

Baseline assessment

Evaluate for HBV or HCV coinfection, diabetes mellitus, hyperlipidemia, cardiovascular disease, smoking, renal disease, other comorbid conditions

Consider drug interactions

Perform resistance testing

Assess for pregnancy

Patient readiness for treatment should be considered when deciding to initiate ART.

Thompson et al, JAMA, 2012.


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Important considerations

ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII)

ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (AIa)

The optimal timing for patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in these patients should be managed in consultation with experts (BIII)


ART is recommended in all HlV-infected persons with tuberculosis (TB) and should be started within 2 weeks of TB treatment when the CD4 cell count is below 50/µL and by 8 to 12 weeks for those with higher CD4 cell counts (Ala).

The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of diagnosis and managed in consultation with experts (BIII).



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CLASS OF HAARTs

Nucleoside RTIs• Zidovudine (ZDV)• Didanosine (ddI)• Stavudine (d4T)• Lamivudine (3TC)• Abacavir (ABC)• Emtricitabine (FTC)

Protease Inhibitors• Saquinavir (SQV)• Ritonavir (RTV)• Indinavir (IDV)• Nelfinavir (NFV)• Lopinavir/r (LPV/r)• Atazanavir (ATV)• Fosamprenavir (Fos-APV)• Tipranavir (TPV)• Darunavir (DRV)

Fusion Inhibitor• Enfuvirtide (T-20)

CCR5 Antagonist• Maraviroc (MVC)

The Initial Regimen

Tenofovir/emtricitabine (TDF/FTC) OR Abacavir/lamivudine (ABC/3TC)

With third agent (NNRTI, boosted PI, or InSTI):

Efavirenz OR

Atazanavir/r OR

Darunavir/r OR

Raltegravir



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2NRTIs + NNRTIs

Efavirenz/tenofovir/emtricitabine (AIa)

Efavirenz plus abacavir/lamivudine (AIa) in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/Ml.


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2 NRTIs + PIs

Darunavir/r plus tenofovir/emtricitabine (AIa)

Atazanavir/r plus tenofovir/emtricitabine (AIa)

Atazanavir/r plus abacavir/lamivudine (AIa) in patients with plasma HIV-1 RNA <100,000 copies/mL

2 NRTIs + Integrase Inhibitor

Raltegravir plus tenofovir/emtricitabine (AIa) .

Alternative to Initial Antiretroviral Regimens

NNRTI plus nRTIs

Nevirapine plus tenofovir/emtricitabine or abacavir/lamivudine (BIa)

Rilpivirine/tenofovir/emtricitabine (or rilpivirine plus abacavir/lamivudine) with baseline plasma HIV-1 RNA < 100,000 copies/mL (BIa)

PI/r plus nRTIs

Darunavir/r plus abacavir/lamivudine (BIII)

Lopinavir/r plus tenofovir (BIa) (or abacavir/lamivudine) (BIa)

InSTI plus nRTIs

Raltegravir plus abacavir/lamivudine (BIIa)

Elvitegravir/cobicistat/tenofovir/emtricitabine** (BIb)


Important Notes

Efavirenz

once daily dose .

must be taken on an empty stomach, preferably at bedtime ( increased efavirenz concentrations observed following administration with food may lead to an increase in frequency of adverse reactions ) .

Dosing at bedtime may improve the tolerability of nervous system symptoms

Psychiatric symptoms, including insomnia, nightmares, confusion, memory loss, and depression, are common , and more serious symptoms such as psychosis may occur in patients with compromised liver or kidney function.


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Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz (EFV) and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV-based regimens(AIII).

Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized after 4 to 6 weeks of pregnancy

Federally approved HIV/AIDS medical practice guidelines. Aids Information. http://aidsinfo.nih.gov/drugs/269/efavirenz/0/professional.


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http://aidsinfo.nih.gov/drugs/269/efavirenz/0/professional

http://aidsinfo.nih.gov/drugs/269/efavirenz/0/professional

Especial Considerations

Severe hepatotoxicity and rash with nevirapine are more common in initial therapy when CD4 cell count is >250/µL in women and >400/µL in men.

Tropism assay to confirm R5 virus should be done before prescribing maraviroc. Maraviroc is not effective in persons who have X4 or dual/mixed X4/R5 virus infection. Few data are available for maraviroc with tenofovir/emtricitabine or abacavir/lamivudine

In patients with or at high risk of cardiovascular disease, avoiding use of abacavir, lopinavir/r, or fosamprenavir/r might be considered (BIIa)



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In patients with reduced renal function, tenofovir should be avoided, or if treatment for HBV coinfection is needed, dosing should be adjusted according to the prescribing information (AIIa)

Given the increased risk of fragility fractures, it may be prudent to avoid tenofovir as part of initial therapy in postmenopausal women (BIIa)

The recommended initial ART regimen in the setting of rifampinbased tuberculosis treatment is efavirenz plus 2 nRTls (AIa)


The recent recommendation for use of a 3-month, once-weekly regimen of isoniazid with rifapentine for treatment of latent TB infection is not recommended for HlV-infected patients receiving ART (BIII).

The ART regimen for HIV- and HBVcoinfected persons should include tenofovir and emtricitabine or lamivudine as the nRTI background (AIIa)



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Patient Monitoring

Plasma HIV-1 RNA levels should be monitored at least every 3 months after treatment is initiated or changed for virologic failure to confirm suppression of viremia below 50 copies/mL (AIa).

CD4 cell count should be monitored at least every 3 months after initiation of therapy, especially among patients with less than 200/µL, to determine the need for primary opportunistic infection prophylaxis (BIII).

Once viral load is suppressed for 1 year and CD4 cell count is stable at 350/µL or greater, HIV-1 RNA and CD4 cell count can be monitored at intervals of up to 6 months in patients with dependable adherence (CIII).


Detectable HIV-1 RNA (>50 copies/mL) during therapy should be confirmed in a subsequent sample between 2 and 4 weeks afterward and prior to making management decisions (BIII)

Sustained elevation of HIV-1 RNA between 50 and 200 copies/mL should prompt evaluation of factors leading to failure and consideration of switching of ART (BIII)

Baseline genotypic testing for resistance should be performed in all treatment-naive patients (AIIa) and in cases of confirmed virologic failure (AIa)



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Therapeutic drug monitoring is not recommended in routine care; however, selected patients (eg, pregnant women, children, and patients with renal or liver impairment) might benefit from this intervention (BIII)

Health care practitioners and health systems should initiate strategies to monitor and improve entry into and retention in care and ART adherence and to incorporate and analyze quality-of-care indicators (CIII)



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Conclusions

Recommendation to begin therapy earlier in asymptomatic persons is informed by

Increased evidence of the harmful effects of uncontrolled viremia and its associated immune activation and inflammation, even at higher CD4 cell counts

Evidence that all HIV-infected adults may benefit from ART

Data showing ART reduces likelihood of transmission of HIV.

ART is recommended and should be offered regardless of CD4 cell count(BIII).

ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII).



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ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (other than cryptococcal and tuberculous meningitis),with attention to drug interactions and the potential for immune reconstitution inflammatory syndrome (IRIS) (AIa).

The optimal timing of ART initiation in patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in patients with cryptococcal meningitis should be managed in consultation with experts (BIII).



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ART is recommended in all HlV-infected persons with TB and should be started within weeks of TB treatment when CD4 cell count is below 50/µL and by 8 to 12 weeks for those with higher CD4 cell counts (AIa).The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of TB treatment and managed in consultation with experts (BIII).


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Antiretroviral Treatment of Adult with HIV Infection The guidelines of International Antiviral Society - USA Panel

Health & Medicine

art initiation

line art

symptoms biii art

hiv transmission

weeks of tb treatment

initiating art early

triple arvs art

important considerations