Antiretrovirals_Harr.. - TREE

Anti-retroviral Therapy, 2012 

Robert Harrington, M.D. 

When to treat 

What to use 

Monitoring & Drug resistance 

New agents and regimens

Case 1 

• A 72 yo male has been your patient for 15 years. He first 

tested + for HIV in 1985. He has never had any HIV related 

problems. His CD4 count has never been below 600 and his 

HIV RNA has never been > 9000. He is ARV naïve. 

• His other medical problems include porphyria, mild HTN, 

osteoarthritis, GERD, chronic dizziness and BPH. 

• He smokes 1ppd (for 50 yrs), doesn’t drink or use illicit drugs. 

His meds include HCTZ, omeprazole, ibuprofen, sildenafil 

and tamsulosin. 

• His family history is notable for longevity – both parents are 

still alive as are 2 siblings.

Case 1 

• At his most recent visit he is cantankerous but without 

worrisome complaints. He has a new partner with whom he is 

sexually active. His partner is HIV negative. 

• His most recent CD4 is 598 and his HIV RNA is 8500. 

• Who wants to start him on anti-retroviral therapy?


When to treat?

HIV Infection: Pathogenesis 

Anti-HIV 

T-cell response 

Sero-conversion 

Antibody response 

Typical Course 

Plasma HIV RNA 

10,000,000 

1,000,000 

100,000 

10,000 

1,000 

100 

10 

Plasma RNA Copies 

CD4 Cells 

Intermediate Stage 

AIDS 

Viral set point 

CD4 Cell Count 

1,000 

500 

1 

A lot of important stuff happens here 

4-8 Weeks Up to 12 Years 2-3 Years

Long Term Non-progression 

HIV-CTL Sero-conversion 

10,000,000 


1,000,000 

100,000 

10,000 

1,000 

100 

CD4 Cells 


1,000 

10 

Plasma RNA 

Copies 

500 

1 

4-8 Weeks Up to 12 Years 2-3 Years 

Some CD4 death, good HIV-CTL, good HIV control

Rapid Progression 

CTL 

response 

Seroconversion 


10,000,000 

1,000,000 

100,000 

10,000 

1,000 

100 

Plasma RNA Copies 

AIDS 


1,000 

10 

CD4 Cells 

500 

1 

4-8 Weeks Up to 12 Years 2-3 Years 

Lots of CD4 death, poor HIV-CTL, poor HIV control

Early Vs Standard HAART in Haiti 

(Severe, et.al NEJM, 2010;263:257-65) 

• Randomized, open label study ARV (AZT+3TC+EFV) 

given when 

– CD4 cells were > 200 and < 350 cells/uL and no h/o 

AIDS Vs 

– CD4 cells were < 200 cells/uL or when patients had a 

clinical AIDS diagnosis 

• N = 816 (408 in each group) 

• Baseline CD4 ~ 280 in each group 

• All patients received TMP/SMX, daily MVI and food 

supplements and those who were PPD + received INH

Early Vs Standard HAART in Haiti 

(Severe, et.al NEJM, 2010;263:257-65) 

23 deaths in the standard Rx group Vs 6 in the early Rx group 

36 incident cases of TB in the standard Rx group Vs 18 in the early Rx group 

Survival 

Incident TB

Impact of Age on Risk of HIV 

Progression 

Predicted 6-Month Risk of Progression to AIDS in 

Patient With HIV RNA of 30,000 c/mL 

Predicted Risk (%) 

Phillips A et al. AIDS. 2004;18:51-58. 

CD4 Cell Count (cells/mm 3 )

Early Vs Deferred HAART 

(Kitahata, et.al NEJM, 2009) 

NA-ACCORD study 

• Observational study of 17, 517 asymptomatic 

patients in US and Canada 

• Two analyses: 

– 1: Start HAART b/n 350-500 Vs deferred. 

• N= 8362, 2084 (25%) started at 350-500, 6278 deferred 

• RR of death for deferred group 1.69 (P 500 Vs deferred 

• N=9155, 2220 (24%) started at > 500, 6935 deferred 

• RR of death for deferred group 1.94 (P

Early Vs Delayed HAART, 2012 

CASCADE Study (Arch Int Med, 2011, 171:1560) 

• Observational cohort study of 9455 ARV naïve patients 

with known date of HIV infection 

CD4 count AHR for AIDS or Death AHR for Death 

0-49 0.32 (0.17-0.59) 0.23 (0.14-0.95) 

50-199 0.48 (0.31-0.74) 0.55 (0.28-1.07) 

200-349 0.59 (0.43-0.81) 0.71 (0.44-1.15) 

350-499 0.75 (0.49-1.14) 0.51 (0.33-0.80) 

500-799 1.10 (0.67-1.79) 1.02 (0.49-2.12)

HAART, 2012: Simple Regimens 

Drugs 

Simple Regimens 

Total daily pill count Dosing 

• RLP/TDF/FTC 1 pills QD 

• R-ATZ - TDF/FTC 3 pills QD 

• R-LPV - TDF/FTC 5 pills QD 

• R-DRV – TDF/FTC 3 pills QD 

• R-FAMP - TDF/FTC 5 pills QD 

• EFV/TDF/FTC 1 pill QD 

• R-LPV - AZT/3TC 6 pills BID 

• EFV - AZT/3TC 3 pills BID 

• RAL – TDF/FTC 3 pills BID

HAART, 2012: Effect on Transmission 

What about his new partner? 

HPTN 052: Immediate vs Delayed ART for HIV 

Prevention in Sero-discordant Couples 

HIV-infected, heterosexual 

sero-discordant 

couples; CD4+ cell count 

of the infected partner: 

350-550 cells/mm 3 

(N = 1763 couples) 

Immediate HAART* 

Initiate HAART at CD4+ cell count 350-550 cells/mm 3 

(n = 886 couples) 

Delayed HAART 

Initiate HAART at CD4+ cell count ≤ 250 cells/mm 3† 

(n = 877 couples) 

• Primary efficacy endpoint: virologically linked HIV transmission 

• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe 

bacterial infection and/or death 

Cohen MS, et al. N Engl J Med. 2011;365:493-505.

HAART, 2012: Effect on Transmission 

HPTN 052: HIV Transmission Reduced by 

96% in Sero-discordant Couples 

Total HIV-1 Transmission Events: 39 

(4 in immediate arm and 

35 in delayed arm; P < .001) 

Linked Transmissions: 

28 

Unlinked or TBD 

Transmissions: 11 

Delayed 

Arm: 27 

Immediate 

Arm: 1 

P < .001 

Cohen MS, et al. N Engl J Med. 2011;365:493-505.

Early Vs Delayed HAART, 2011 

CASCADE Study (Lodi, CID, 2011, 53:817) 

• Observational cohort study of 9455 ARV naïve patients 

with known date of HIV infection 

• Analyzed time from seroconversion to CD4 threshholds 

Median time to < 500: 1.2 yrs 

Median time to < 350: 4.2 yrs 

Median time to < 200: 7.9 yrs

CD4 Count, Viral Load and Clinical Course 


10,000,000 

1,000,000 

100,000 

10,000 

1,000 

100 

10 

1 

Plasma RNA 

Copies 

1996 and 2012: Treat Everyone! 

2009-2011 

2001 

2004-5 


500 

- 350 

- 200 

4-8 Weeks Up to 12 Years 2-3 Years

When to Treat? 

• Prevent Immune system destruction 

• More effective when started early 

• Mortality benefit even at high CD4 

• Prevent clinical “events” 

• Prevent transmission & truncate the 

epidemic 

Early 

• Toxicities of treatment 

• Increased risk of resistance 

• Low rate of disease progression? 

• Cost 

Later

DHHS Guidelines 2012: When To Treat 

ART is recommend for all HIV infected patients: only the strength of 

the recommendation varies by CD4 count 

CD4+ Cell Count 

• < 350 cells/mm³ 

• 350-500 cells/mm³ 

• > 500 cells/mm³ 

Recommendation 

• Start ART (AI) 

• Start ART (AII) 

• Start ART (BIII) 

Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count 

• History of AIDS-defining illness (AI) 

• Pregnancy (AI) 

• HIV-associated nephropathy (AII) 

• HBV co-infection (AII) 

• Patients at risk of transmitting HIV to sexual partners (AI, heterosexuals; AIII, others) 

• HCV co-infection* (BII) 

• Patients > 50 years of age (BIII) 

DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012.

WHO Guidelines 2010: When To Start 

Population Clinical condition Recommendation 

• Asymptomatic (including 

pregnant women) 

• Symptomatic (including 


• Symptomatic (including 


• WHO stage 1 

• WHO stage 2 

• WHO stage 3 or 4 

• < 350 cells/mm³ 

• < 350 cells/mm³ 

• Any CD4 cell count 

Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count 

• HBV co-infection requiring therapy 

• Active tuberculosis 

• Any CD4 cell count


Should ARV treatment be started in the 

setting of an acute opportunistic infection?

Case 2 

• A 38 yo African male immigrant presents to HMC 

ED with a 10 kg weight loss, 10 weeks of cough 

and intermittent fever. He has no past medical 

history. 

• On exam he is thin, T 38.8 C, BP 100/70, HR 104, 

RR 20. He has prominent cervical adenopathy, 

oral thrush and course breath sounds over his R 

upper and mid lung zones.

Case 2 

• An HIV test is + and Sputum smear stains 3+ for AFB

Case 2 

• He is admitted to the hospital, placed in isolation 

and started on “RIPE” therapy. 

• After a week his constitutional symptoms 

improve. His CD4 T-cell count measures 15 

cells/uL. 

• Who wants to prescribe HAART now?

Tuberculosis and HAART

Tuberculosis and HAART 

Study Patients ARV timing IRIS Outcome 

Blanc 

(Cambodia) 

Havlir 

(Africa, Asia, 

NA, SA) 

Karim 

(S. Africa) 

N = 661 

Median CD4 = 25 

N = 809 


N = 642 


2 weeks Vs 

8 weeks 

Median of 10 

Vs 70 days 

Median of 21 

Vs 97 days 

HR 2.51 (for 

early ARVs) 

Early 11% 

Late 5% 

HR of 2.62 

(for early 

ARVs) 

HR for death 0.62 (for 

early ARVs) 

Death rate: Overall 

12.9% Vs 16.1% (NS) 

CD4 < 50: 15.5% Vs 

26.6% (P=0.02) 

AIDS or Death: 

Overall: No difference 

CD4 < 50: 8.5 Vs 26.3 

per 100 py (P=0.06)

Tuberculosis and HAART 

Blanc, Cambodia Havlir, Africa, Asia, NA, SA Karim, South Africa

Early Vs Delayed HAART in Patients with 

Cryptococcal Meningitis in Africa 

(Macadzange, CID, 2010;50:1532-38) 

• Open Label RCT 

• Patients: Adults with HIV and Crypto meningitis (CSF CrAg 

or India ink positive) 

• All received Fluconazole 800 mg PO once daily x 10 wks + 

aggressive pressure management 

• Followed by maintenance fluconazole 200 mg 

• Intervention: d4T, 3TC, NVP 

– EARLY: Immediate start within 72 hours of diagnosis of 

cryptococcal meningitis 

– DELAYED: Start after initial 10 wks of fluconazole 

• Primary Outcome: Mortality after 2 years




TOTAL: 50 patients 

Overall 2-yr Mortality: 62% 

EARLY 

27 patients 

Median Survival: 35 days* 

2-yr Mortality: 87%** 

DELAYED 

23 patients 

Median Survival: 274 days 

2-yr Mortality: 37% 

*Comparison of median survival, p=0.03 

**Comparison of 2-yr Mortality, p=0.002



(Macadzange, CID, 2010;50:1532-38)




Cause of death Early treatment Delayed treatment 

Cryptococcal meningitis 

alone 

Cryptococcal meningitis 

+ another diagnosis 

14 8 

5 2 

Other diagnoses alone 4 2 

Total # of deaths 23 10

Cryptococcal Optimal ART Timing (COAT) 

Trial 

BULLETIN: HIV Treatment Study in Patients with Cryptococcal 

Meningitis Ends Enrollment Early: 

• Higher Mortality Rate Found with Early Antiretroviral Therapy. NIAID is ending 

enrollment in its “Cryptococcal Optimal ART Timing” (COAT) study because of 

higher mortality rates among participants in one of the two HIV treatment arms. 

The Phase IV study began in November 2010. It was evaluating whether HIVinfected 

participants hospitalized with cryptococcal meningitis (CM) but not yet 

taking antiretroviral therapy (ART) would improve their chances of survival if they 

began ART while receiving CM treatment as inpatients (7-11 days) compared with 

the standard practice of beginning ART as outpatients, approximately five weeks 

after receiving CM treatment. 

• Two reviews of the COAT trial’s safety and effectiveness data last month by DSMB 

found substantially higher mortality rates among the 87 participants who received 

early ART compared with the 87 participants who received delayed HIV treatment.

Starting HAART in the setting of an OI 

• The initiation of HAART in the setting of most 

OIs should not be delayed beyond 2 to 8 weeks 

• Concerns about precipitating IRIS are 

overdone 

• Cryptococcal meningitis is an exception

HIV: Anti-retroviral Therapy, 2012 

The decision is made to treat both patient 

#1 and #2 

What are appropriate regimens for these 

patients?

Antiretroviral Therapy 

Five Drug Classes 

• Nucleoside Reverse Transcriptase Inhibitors (NRTI) 

• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) 

• Protease Inhibitors (PI) 

• Integrase Inhibitors 

• Cell Entry Inhibitors

HIV Life Cycle


NUCLEOSIDE REVERSE TRANSCRIPTASE 

INHIBITORS (NRTIs) 

AZT (zidovudine; Retrovir) 

3TC (lamivudine; Epivir) 

d4T (stavudine; Zerit) 

ddI (didanosine; Videx) 

Abacavir (Ziagen) 

ddC (zalcitabine; Hivid) 

Tenofovir (Viread)* 

Emtricitabine (Emtriva)


NON-NUCLEOSIDE REVERSE 

TRANSCRIPTASE INHIBITORS (NNRTIs) 

Efavirenz (Sustiva) 

Nevirapine (Viramune) 

Delavirdine (Rescriptor) 

Etravirine (Intelence) 

Rilpivirine (Endurant) 

Efavirenz + Tenofovir + FTC (Atripla) 

Rilpivirine + Tenofovir + FTC (Complera)


PROTEASE INHIBITORS 

Ritonavir (Norvir) 

Saquinavir (Fortavase; Invirase) 

Nelfinavir (Viracept) 

Indinavir (Crixivan) 

Fosamprenavir (Lexiva) 

Lopinavir/ritonavir (Kaletra) 

Atazanavir (Reyataz) 

Tipranavir (Aptivus) 

Darunavir (Prezista)


INTEGRASE INHIBITORS 

Raltegravir (Isentress) 

• Only member of its class, twice a day medicine 

• Initially approved for salvage therapy, now 

recommended as a preferred drug for initial 

treatment


CELL ENTRY INHIBITORS 

T-20 (Enfuvirtide) 

• Synthetic peptide – blocks gp41 mediated fusion 

• Subcutaneous injection twice/day 

• Indicated for “salvage therapy” (use with at least one other active drug or in 

patients with high risk of disease progression/death) 

Maraviroc (Selzentry) 

• Only effective against HIV isolates that utilize CCR5 co-receptor 

• Must screen patients for the absence of CXCR4 using virus 

• Not clear where to use it since “salvage patients” more likely to have CXCR4 

virus

Initiating Antiretroviral Therapy 

DHHS Recommendations (2012) 

Preferred Regimens 

NNRTI-Based 

EFV QD 

PI-Based 

Atazanavir/R QD 

Darunavir/R QD 

Integrase-Based 

Raltegravir BID 

+ TDF/FTC 

+ TDF/FTC 

+ TDF/FTC 

+ TDF/FTC

NNRTI or PI or Raltegravir? 

NNRTIs 

• High efficacy 

• Simplicity—lowest pill 

burden 

• Relatively well tolerated 

• Limited toxicity 

• Low genetic barrier to 

resistance 

• Drug-drug interactions 

PIs 


• Getting simpler, but 

regimen ≥3 pills per day 

• High genetic barrier to 

resistance 

• Relatively well tolerated 

except for GI 

• Fat accumulation and lipid 

problems persist 

• Drug-drug interactions, 

especially with RTV 

GI = gastrointestinal; RTV = ritonavir. 

Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: 

http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.

NNRTI or PI or Raltegravir? 


Raltegravir 

• Very well tolerated (maybe increased 

depression?) 

• No Drug-drug interations 

• Low genetic barrier to resistance 

• BID dosing


WHO Recommended ARV Regimens 

1 st line AZT or TDF 

+ 

3TC or FTC 

(phase out d4T use) 

2 nd line AZT or TDF 

(choice dictated by 1 st regimen) 

+ 

3TC or FTC 

nRTI nnRTI R-PI Other 

NVP 

or 

EFV 

R-ATZ 

or 

R-LPV 

3 rd line 2 nRTIs R-DRV or 

Etravirine or 

Raltegravir


Review of the Efficacy of TDF-Containing Regimens 

WHO TDF 

Regimens 

Comparator Regimens 

TDF/3TC/NVP AZT/3TC/NVP TDF/FTC/EFV Inferior 

Outcome – c/w 

comparator arms 

TDF/FTC/NVP TDF/FTC/ATZr TDF/FTC/EFV 

AZT/3TC NVP TDF/FTC/LPVr 

TDF/3TC/EFV D4T/3TC/NVP AZT/3TC/EFV 

TDF/3TC/RAL AZT/3TC/LPVr 

DDI/3TC or ABC/EFV 

TDF/FTC/EFV 

AZT/3TC/EFV ABC/3TC/EFV 

TDF/FTC/RAL TDF/FTC/ATZr 

ABC/3TC/ATZr TDF/FTC/NVP 

TDF/FTC/RLP ELV/COB/FTC/TDF 

RAL/LPVr TDF/3TC/NVP 

ABC/3TC/EFV 

Equivalent or inferior 

Equivalent 

Equivalent or superior 

Not all TDF regimens are equal! 

(Tang, CID 2012;54:862-75)

HIV: Anti-retroviral Therapy, 2012 

Monitoring patients and drug resistance

Case 3 

• A 38 year old man with AIDS was started on HAART 

(EFV, TDF, FTC) a year ago with an excellent response: 

his HIV RNA dropped from 248,000 copies to < 30 copies 

and his CD4 increased from 87 to 360 cells. 

• Unfortunately, he’s missed several recent appointments 

and when he finally does make it to the office you find he 

has thrush and seborrheic dermatitis. His CD4 count has 

decreased to 240 cells and his HIV RNA is now detectable 

at 37,000 copies. 

• What is going on? 

• What, in particular, are you worried about?

Antiretroviral Therapy, 2012 

Poor potency 

Wrong dose 

Host genetics 

Social/personal issues 

Regimen issues 

Toxicities 

Poor adherence 

Poor absorption 

Rapid clearance 

Poor activation 

Drug interactions 

Insufficient drug level 

Viral replication in the 

presence of drug 

Resistant virus

Adherence and Drug Resistance Relationship 

Resistance 

1 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

0 10 20 30 40 50 60 70 75 80 85 90 95 100 

Adherence

When to Use Resistance Testing 

Patient Status IAS-USA 1 DHHS 2 European 3 

Primary/acute Recommend Recommend ‡ Recommend 

Post-exposure prophylaxis — — Recommend 

Chronic, treatment naïve Consider* Recommend ‡ 

Strongly 

consider* 

Failure Recommend Recommend Recommend 

Pregnancy Recommend † Recommend Recommend † 

Pediatric — — Recommend † 

*Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug 

resistance in untreated patients ≥5% (European: ≥10%); † When viral load is detectable; ‡ December 1, 

2007: The panel recommends performing genotypic drug resistance testing for all treatment-naïve 

patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated. This 

recommendation is based on the fact that transmitted resistance mutation may be detected at a time 

point more proximal to the time of infection than later. Repeat testing may be considered at the time 

when therapy is to be initiated. 

1. Hirsch MS et al. Clin Infect Dis. 2003;37(1):113-128; 2. Adapted from US Department of Health and Human Services 

Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. 

Accessed March 13, 2008; 3. Vandamme AM et al. Antivir Ther. 2004;9(6):829-848.

Overview of Antiretroviral 

Resistance Testing 

How do we test for resistance? 

Genotype: most common, least 

expensive 

Phenotype: useful for viruses 

with multiple PI mutations 

Virtual Phenotype: less expensive 

than a phenotype

WHO Monitoring Guidelines 

• All patients should have access to CD4 

testing to optimize ARV management 

• HIV RNA testing is recommended to 

confirm treatment failure 

• No recommendation for drug resistance 

testing

WHO Monitoring Guidelines 

Treatment Failure 

• Clinical: New or recurrent stage 4 condition 

• Immunologic: 

– CD4 < baseline OR 

– CD4 decline of 50% from peak OR 

– CD4 never > 100 

• Virologic: HIV RNA > 5000 copies

WHO: When to Switch

Monitoring Patients on ARVs 

DART 

• 3321 ARV naïve 

patients in Uganda and 

Zimbabwe 

• Randomized to 

– Clinical monitoring 

– Clinical and laboratory 

monitoring (CD4 

counts) 

Fewer deaths and stage 4 events 

with CD4 monitoring 

(Lancet 2010, 375; 9703: 123-131)


• Randomized clinical trial 

in rural Uganda 

• 1093 subjects 

– Clinical arm 

– CD4 arm 

– CD4 and HIV RNA 

Time to first severe morbidity event or death, 

per protocol analysis excluding first 90 days of 

ART 

• Higher rate of death or 

progression in the 

clinical arm than in the 

CD4 or HIV RNA arms 

Mermin J et al. BMJ 2011;343:bmj.d6792


• Observational study of the 

performance of CD4 criteria to 

predict virologic outcomes 

• 9690 patients in Nigeria 

• Failure 

– 1225 both immunologic and 

viral 

– 872 viral only 

– 1897 immunologic only 

• Sensitivity of CD4 to predict VF = 

58% 

• Specificity of CD4 to predict VF = 

75% 

• PPV of CD4 to predict VF = 39% 

• Among those with both IF and VF: 

VL criteria detected failure sooner 

Probability of NO Regimen Failure (by 

any criteria) if using either VL or CD4 

monitoring 

(Rawizza, CID 2011;53:1283-90)

Resistance from the Beginning 

Hammers, Lancet Infectious 

Diseases 2011; 11:750-59 

• Cross-sectional study of 2436 

patients starting ARVs between 

2007-09 in Kenya, Nigeria, 

South Africa, Uganda, Zambia 

and Zimbabwe 

• Genotypes on pre-treatment 

specimens were performed 

• Overall rate of drug resistance 

was 5.5% (range 1.1-12.3%) 

• OR for each additional year 

since roll out of ARVs: 1.38 

More drug resistance in Uganda – likely 

Due to earlier roll-out of ARV therapy

Resistance after Failure 

Sigaloff, Lancet Infectious 

Diseases 2011; 11:769-79 

• Review of 30 studies reporting on 

3241 children in resource limited 

settings (Latin America, Asia and 

Africa) 

• Looked for Resistance Associated 

Mutations (RAMs) in patients 

failing first line regimens 

• Overall treatment failure in 40% of 

children

Drug Resistance 

• ARV treatment 

without viral load 

monitoring and 

without drug 

resistance testing? 

• Like the optimist who 

falls from the top of 

the empire state 

building: 

As he’s falling past the 50 th 

floor he thinks, 

“So far, so good!”

Antiretroviral Therapy, 2012 

What do we do when our patients are 

intolerant of or failing an ARV regimen? 

We give them a different regimen!

New Meds or Regimens 

• GS-7340: new pro-drug of tenofovir 

• Rilpivirine: an alternative to EFV (Complera Vs Atripla) 

• Etravirine: probably as good as EFV with fewer AEs 

• Elvitegravir: New once a day integrase inhibitor – will be 

part of the new “Quad pill” (ELV+cobicistat+TDF+FTC) 

• Dolutegravir: Promising once a day integrase inhibitor 

Nuc-sparing regimens? 

• Raltegravir + R-DRV: nuc-sparing regimen, surprisingly 

high failure rate 

• Maraviroc + R-ATZ: effective and avoids NRTIs 

• TRIO: salvage with RAL + ETR + DRV

GS-7340: Antiviral Activity of Novel 

Prodrug of Tenofovir 

• Lower TDF plasma concentrations, higher intracellular concentrations 

obtained with GS-7340 vs TDF 

– Hypothesized that this may result in greater efficacy, reduced toxicity 

• Previous study evaluated higher doses of GS-7340: 50 mg and 150 mg [1] 

HIV-infected 

treatment-naive or - 

experienced patients with no 

genotypic resistance to TDF, 

HIV-1 RNA ≥ 2000 copies/mL, 

CD4+ count ≥ 200 cells/mm 3[2] 

(N = 38) 

TDF 300 mg QD 

(n = 6) 

GS-7340 8 mg QD 

(n = 9) 

GS-7340 25 mg QD 

(n = 8) 

GS-7340 40 mg QD 

(n = 8) 

GS-7340 Placebo QD 

(n = 7) 

1. Markowitz M, et al. CROI 2011. Abstract 152LB. 2. Ruane PJ, et al. CROI 2012. Abstract 103.

New Formulation of Tenofovir (GS-7340) 

Median DAVG 11 (1 o endpt.)* 

P vs placebo 

TDF 

300 mg 

N=6 

-0.48 

.038 

7340 

8 mg 

N=9 

-0.76 

0.021 

7340 

25 mg 

N=8 

-0.94 

0.017 

7340 

40 mg 

N=8 

-1.08 

0.01 

No premature drug d/c, -associated SAEs, significant lab 

abnormalities; most AEs mild-moderate 

Placebo 

N=7 

-0.01 

--- 

Median VL log 10 change ~1.0 ~1.0 ~1.5 ~1.5 NS 

C max plasma vs Tenofovir --- 98% 94% 89% --- 

AUC vs Tenofovir --- 96% 86% 79% --- 

PBMC intracellular TFV-DP --- 1x 7x 20x --- 

GS-7340: better antiviral activity with 1/10 th TDF’s 

mass (potential for single tablet regimens) 

P Ruane et al, CROI 2012, Abstract 103 

*Time-weighted average change in HIV RNA after 10 days

Greater Antiviral Activity of GS-7340 

25 mg and 40 mg vs TDF 

Median HIV-1 RNA Change 

(log 10 c/mL) 

0.5 

0.0 

-0.5 

-1.0 

-1.5 

-2.0 

0 

Dosing 

10 20 

Day 

Placebo (n = 7) 

TDF 300 mg (n = 6) 

GS-7340 8 mg (n = 9) 

GS-7340 25 mg (n = 8) 

GS-7340 40 mg (n = 8) 

• Higher intracellular tenofovir diphosphate levels and lower 

circulating plasma tenofovir levels with GS-7340 vs TDF 

Ruane PJ, et al. CROI 2012. Abstract 103.

Case 4 

• A 32 yo male, recently diagnosed with HIV 

• Baseline CD4 340, HIV RNA 95,000 copies 

• H/o of depression with suicidality 

• Wants a one pill once-a-day regimen 

• Today’s date is July 19, 2012 

• What ARV regimen could you offer him? 

– TDF/FTC/Rilpivirine (Complera) 

– Etravirine + TDF/FTC 

– Quad (Elvitegtravir/cobisistat/TDF/FTC)

Rilpivirine: ECHO, THRIVE: Response to 

RPV vs EFV in Pts With High VL, Low CD4 

• Reduced response to RPV vs EFV at VL > 100,000 

copies/mL and CD4+ cell counts < 200 cells/mm³ 

Rilpivirine 

EFV 

HIV-1 RNA < 50 copies/mL at Wk 48 by Baseline VL 

100 

80 

6.6 (1.6-11.5) 

90 

84 

90 

83 

91 

84 

-3.6 (-9.8 to +2.5) 

100 

81 

80 77 

76 

82 

79 80 

Patients (%) 

60 

40 

20 

0 

332/ 

368 

276/ 

330 

Pooled 

162/ 

181 

136/ 

163 

ECHO 

170/ 

187 

140/ 

167 

THRIVE 

Patients (%) 

60 

40 

20 

0 

246/ 

318 

285/ 

352 

Pooled 

125/ 

165 

149/ 

181 

ECHO 

121/ 

153 

136/ 

171 

THRIVE 

≤ 100,000 copies/mL 

> 100,000 copies/mL 

48 weeks: Patients with BL CD4 < 50: HIV RNA < 50: RLP 59%, EFV 81% 

Cohen C, et al. AIDS 2010. Abstract THLBB206. Cohen C, et al. Lancet. 2011;378:229-237. 

Molina JM, et al. Lancet. 2011;378:238-246. Cohen C, et al. CROI 2012. Abstract 626.

Case 4 

• A 32 yo male, recently diagnosed with HIV 

• Baseline CD4 340, HIV RNA 95,000 copies 

• H/o of depression with suicidality 

• Wants a one pill once-a-day regimen 






Case 5 

• A 43 yo treatment experienced male 

• CD4 40, HIV RNA 240,000 copies 

• Intolerant of all protease inhibitors 

• Regimen has to be once a day 

• Failed Atripla with K103N 






SENSE: Phase 2: Etravirine vs Efavirenz 

• MC, R, PC trial of 157 pts 

• ETV (400 QD) + 2NRTI Vs 

EFV (600 QD) + 2NRTI 

• Baseline 

– CD4: 302 cells/uL 

– HIV RNA: 4.8 logs 

• Results 

2:1 

– Neuropsych AEs: ETR 

6.3%, EFV 21.5% 

– Failure/resistance 

• ETR: 4/0 

• EFV: 7/3 

– < 50: ETR 79%, EFV 76% 

(Gazzard, AIDS, 2011; 25:2249-58) 

< 50 at 48 Weeks 

Planned 

Duration 

Week 240

Case 5 











Case 6 




• Failed Atripla with RT mutations: (Y181C, Y188C, 

G190S) 


• Today’s date is September 1, 2012 





The Quad Pill: Elvitegravir/Cobicistat/TDF/FTC 

Vs Atripla or R-ATZ + Truvada 

HIV-infected 

treatment-naive patients with 


any CD4+ cell count, 

CrCl ≥ 70 mL/min 

(N = 700) 

Elvitegravir/Cobicistat/TDF/FTC QD 

+ EFV/TDF/FTC placebo QD 

(n = 348) 

EFV/TDF/FTC QD 

+ Elvitegravir/Cobicistat/TDF/FTC placebo QD 

(n = 352) 

HIV-infected 

treatment-naive patients, 


any CD4+ cell count, 

CrCl ≥ 70 mL/min 

(N = 708) 

Elvitegravir/Cobicistat/TDF/FTC QD 

+ ATV/RTV + FTC/TDF placebo QD 

(n = 353) 

ATV/RTV + TDF/FTC QD 

+ Elvitegravir/Cobicistat/TDF/FTC placebo QD 

(n = 355) 

DeJesus E, et al. CROI 2012. Abstract 627. 

Sax P, et al. CROI 2012. Abstract 101.

“Quad” Vs Atripla 48 wks 

• Randomized double-blind placebo-controlled 

Research Helps 

Help Research 

Quad 

Atripla 

Premature D/C 11% 13% Similar reasons 

% VL

“Quad” Vs R-ATZ+Truvada 48 wks 

CD4 • Randomized Change double-blind +207 placebo-controlled 

+211 P = NS 


Help Research 

Quad 

R-ATZ 

% VL 0.05 

P > 0.05 

Quad is non-inferior virologically and well tolerated

Case 6 




• Failed Atripla with RT mutations: (Y181C, Y188C, 

G190S) 


• Today’s date is September 1, 2012 





Phase 2b: Dolutegravir vs Efavirenz 96wksat 

• Dolutegravir: once daily integrase inhibitor, 

no need for Primary boosting, low PK variability 

Endpoint 

Week 16 

• Randomized, partially blind, dose-finding study 

Planned 

Duration 

Week 240 

• Pts: ARV-naive, 86% men, 80% white 

mean CD4 324, VL 4.5 log 10 , 21% VL>100K 

200 HIV+ pts. 

67%: TDF/FTC 

33%: ABC/3TCh 

America 

2:1 

Dolutegravir 10 mg + 2 NRTIs 



Efavirenz 600mg + 2 NRTIs 

H-J Stellbrink CROI 2012, Abstract 102LBal., CROI 2010, Abstract 514.

Phase 2b: Dolutegravir versus Efavirenz 96 wks 

Premature D/C 

DTV 

10mg 

DTV 

25mg 

• Randomized double-blind placebo-controlled 


Help Research 

DTV 

50mg 

No differences 

EFV 

600mg 

% VL

Case 7 

• A 54 yo highly treatment experienced male 


• Resistant to TDF (K65R), FTC (M184V) 

• Severe lipoatrophy 

• Failed Atripla with RT mutations: (L100I, Y181C, 

G190S) 


– RAL + R-DRV 

– RAL + R-ATZ 

– RAL + R-DRV + FTC 

– MRV + R-ATZ 

– RAL + R-DRV + ETR

Clinical Trials of NRTI-Sparing Regimens 

Raltegravir 

Boosted PI 

+ 

OR 

Maraviroc 

TRIO = 

Raltegravir + Etravirine + Darunavir

ACTG 5262: RAL + R-DRV 

• Single arm study of DRV/R (800/100) + RAL 

(400 bid) 

• N = 112 

• Virologic failure at week 48 = 26% 

• Virologic failure associated with BL VL > 

100,000 

• 5/25 with VF who had genotype performed 

showed integrase mutations (all had BL VL > 

100,000)

Case 7 




• Severe lipoatrophy 

• Failed Atripla with RT mutations: (L100I, Y181C, 

G190S) 


– RAL + R-DRV - No 

– RAL + R-ATZ – Probably No 

– RAL + R-DRV + FTC – Probably No 

– MRV + R-ATZ – Not sure 

– RAL + R-DRV + ETR - No

Case 8 





• Failed Atazanavir (N88S) 







ARNS 139: TRIO Study 

• Observational study 103 patients failing HAART 

with 3 class resistant HIV (but not R to RAL or 

ETV or DRV) 

• Treated with RAL+ETV+DRV with OBR (12% 

on T-20) 

• Results: at 48 weeks 86% were < 50 

CLIN INFECT DIS 49(9):1441-1449.

ARNS 139: TRIO Study 

Percent with VL < 50 

CD4 and VL on Treatment 

CLIN INFECT DIS 49(9):1441-1449.

Case 8 





• Failed Atazanavir (N88S) 







Conclusions 

• All HIV infected patients should be offered ARVs, although 

the strength of this recommendation is influenced by their CD4 

count, age, viral load, whether they have HIV associated 

nephropathy, chronic HBV and the serostatus of their sexual 

partners. (US guideline) 

• Therapy should started early in the course of treatment of most 

OIs (Cryptococcal meningitis being an exception) 

• TDF/FTC in once-daily fixed-dose combination plus an EFV 

or ATZ/r or DRV/r or RAL are proven and preferred initial 

choices (US guideline) 

• New drugs and regimens with high effectiveness, fewer AEs 

and convenient dosing are around the corner, but effective 

NRTI-sparing regimens are not yet proven: one exception: 

• The combination of RAL + ETR + R-DRV is highly effective 

salvage treatment

Madison Clinic Website 

www.madisonclinic.org

Antiretrovirals_Harr.. - TREE

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