Jill Blumenthal, M.D., of UC San Diego AntiViral Research Center, presents "International AIDS Conference 2014: A Moderately Rapid Review" at AIDS Clinical Rounds

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and other infectious diseases of global significance.
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AIDS CLINICAL ROUNDS

2. International AIDS Conference 2014:
A Moderately Rapid Review
Jill Blumenthal, MD
AIDS Rounds
8/8/2014

3. Overview
• HIV
• HCV
• PrEP
• Most Innovative Implementation
Strategies

12. HIV

13. MODERN Study - Maraviroc (MVC) Once Daily With
Darunavir/Ritonavir(DRV/r) Compared to
Tenofovir/Emtricitabine (TDF/FTC) With DRV/r: 48-
Week Results
• Why MVC + boosted PI regimen?
– Nucleoside toxicity-sparing
– Daily regimenimproved adherence
– Low risk of resistance and preservation of rx
options if virologic failure occurs
– MOTIVATE and PK studies support use of MVC
150mg daily with selected ritonavir-boosted PIs
– Prevalence of CCR5 tropic virus greatest in
treatment-naive

16. Conclusions
• MVC 150mg daily in 2-drug rx regimen showed
statistically lower rates of viral suppression when
compared to 3-drug regimen of TDF/FTC + DRV/r
in naïve subjects over 48 weeks
– termination of study 10/13
• Comparable efficacy by tropism assay used at
screening
• Majority of PDTFs failed with VL <400 c/mL
• No treatment-emergent resistance in either arm
• Comparable safety and no unexpected safety
findings

17. HARNESS study: ritonavir-boosted atazanavir
(ATV/r)+raltegravir (RAL) switch study in virologically
suppressed, HIV-1-infected patients
• NRTIs widely used but associated with
development of resistance and toxicity/poor
tolerability
• HARNESS study conducted to evaluate NRTI-
sparing regimen
• Randomized 2:1, open-label, 48-wk,
multinational study evaluating switch from 3-
drug therapy (including 2 NRTIs) to ATV/r
300/100mg daily + RAL 400mg BID

21. Conclusions
• Switching to ATV/r+RAL was well tolerated but
resulted in higher incidence of virologic rebound
than in ATV/r+TDF/FTC group at 24 and 48 weeks
• At week 24, 5 of 7 patients who experienced
virologic rebound in ATV/r+RAL arm had low-level
viremia
• Major INSTI drug resistance mutations occurred
in 1 patient treated with ATV/r+RAL regimen

22. Dolutegravir versus raltegravir in antiretroviral-
experienced, integrase-inhibitor-naive adults with
HIV: week 48 results from the SAILING study
• DTG shown to be effective in ART-naïve (SPRING-2 and
SINGLE) and INI-resistant subjects (VIKING-3)
• SAILING is a phase 3, randomized 1:1, double-blind,
active-controlled, non-inferiority study
• Eligible patients had two consecutive VL > 400 c/ml,
resistance to two or more classes of antiretroviral
drugs, and had 1-2 fully active drugs for background
therapy.
• Received either daily DTG 50 mg or BID RAL 400 mg,
with investigator-selected background therapy.
• Primary endpoint was proportion of patients with VL <
50 c/mL at week 48

27. Conclusions
• DTG once daily had higher virologic efficacy when
compared to RAL bid in experienced, INI-naïve
population
– 71% on DTG vs 64% on RAL had VL < 50 c/mL at wk 48
• Similar tolerability and safety profile
• Statistical superiority driven by fewer withdrawals
due to lack of efficacy, fewer protocol-defined
virologic failures and lower rx-emergent
resistance

28. Major HIV Headlines
• No Detectable HIV RNA or DNA in 2 allogeneic HSCT
Australian Patients Still on ART
• SALT study: As maintenance therapy, ATV/r plus 3TC
was non-inferior to ATV/r plus 2 NRTIs
• OLE study: As maintenance therapy, LPV/r plus 3TC
was non-inferior to LPV/r plus 2 NRTIs
• Less frequent HIV VL monitoring not a/w higher risk of
treatment failure among immunologically stable HIV+
on ART
• HIV RNA between 20-50 c/mL did not increase risk of
treatment failure compared to those with HIV RNA < 20
c/mL.

29. Major HIV Headlines (cont)
• SPANC study: Australian study found that more than
half of HSIL lesions regressed spontaneously, making
the optimal treatment uncertain.
• CHARTER cohort analysis: Not taking ART, markers of
poor general health, and neuropsychiatric
comorbidities predicted faster neurocognitive decline
• Male medical circumcision is associated with a
reduction of HIV incidence among women in South
Africa where MMC roll-out is ongoing (ANRS-12126)
• HDAC inhibitor romidepsin is safe and effectively
reverses HIV-1 latency in vivo as measured by standard
clinical assays

30. HCV

31. All-oral therapy with sofosbuvir plus ribavirin for the
treatment of HCV genotypes 1, 2, 3 and 4 infection in
patients co-infected with HIV (PHOTON-2)
• Sofosbuvir (SOF)- NS5B nucleotide polymerase
inhibitor with pan-genotypic antiviral activity
– high barrier to resistance
– 400mg PO daily
• Co-infected patients need effective IFN-free
HCV therapy that can be safely given with ART
• Endpoints
– SVR12
– Safety

38. Conclusions
• SVR rates high (>85%) for all genotypes
– In G1 treatment-naïve, SVR12 rates significantly higher
in noncirrhotics
– In G2-4 with cirrhotics vs noncirrhotics, not as much
difference
• No S282T mutations detected by deep
sequencing
• SOF well-tolerated with low rate of rx
discontinuations due to AEs
• SOF + RBV effectively co-administered with
TDF/FTC + ATV/r, DRV/r, RPV or RAL

39. SAPPHIRE-II Subgroup Analysis: ABT-450/r/Ombitasvir (ABT-267), Dasabuvir
(ABT-333), and Ribavirin Regimen Achieves High Sustained Virologic Response
Rates 12 Weeks Post-treatment in Treatment-experienced Patients With
Chronic HCV GT 1 Infection, Regardless of Baseline Characteristics
• ABT-450 is an HCV NS3/4A PI
– Co-dosing with ritonavir increases peak, trough and overall
drug exposures
• Ombitasvir (ABT-267) is NS5A PI
• Dasabuvir (ABT-333) is NS5B RNA polymerase inhibitor
• Safety and efficacy from SAPPHIRE-II with 12 week
regimen in non-cirrhotic, treatment-experienced
patients with chronic HCV GT1 previously reported
SVR12 rate 96.3%
• Logistic regression analysis to explore association
between subgroup variables and SVR12

42. Conclusions
• 96.3% of 297 experienced GT-1 infected
patients treated with ABT-450/r/ombitasvir,
dasabuvir and RBV achieved SVR12
• SVR12 rates high across subpopulations
• Among subgroup variables analyzed in logistic
regression model, only baseline VL a/w
likelihood of achieving SVR12

43. TURQUOISE-I: SAFETY AND EFFICACY OF ABT-
450/R/OMBITASVIR, DASABUVIR, AND RIBAVIRIN IN
PATIENTS CO-INFECTED WITH HEPATITIS C AND HIV-1

45. Conclusions
• IFN-free 3D + RBV in co-infected patients,
naïve and experienced, cirrhotics vs non-
cirrhotics
– SVR12 of 93.5% with 12 weeks of therapy
– SVR4 of 96.9% with 24 weeks of therapy
– When coadministered with ATV or RAL, well-
tolerated with no treatment-emergent serious
adverse events

46. Ledipasvir/Sofosbuvir is Safe and Effective as a Single-Tablet-
Regimen for Treatment of Patients with Genotype 1 Chronic
Hepatitis C Virus, Including those with Compensated Cirrhosis
• Ledipasvir (LDV)- NS5A inhibitor with
picomolar potency against GT1a and 1b; 90mg
PO daily
• Sofosbuvir (SOF)- NS5B nucleotide polymerase
inhibitor with pan-genotypic antiviral activity;
high barrier to resistance; 400mg PO daily
• LDV/SOF FDC- combination 90/400mg PO
daily; no food effect

51. Conclusions
• 97% of GT-1 pts in LDV/SOF phase III study
achieved SVR
– Ion-1: LDV/SOF for 12 weeks achieved SVR12 of 99%
in GT-1 naïve and 94% among those w/ cirrhosis
– Ion-3: LDV/SOF for 8 weeks achieved SVR12 of 94% in
GT-1 naïve without cirrhosis
– Ion-2: LDV/SOF for 12 weeks achieved SVR12 of 94%
in GT-1 who failed PegIFN + RBV + HCV Pis
• Adding RBV did not increase SVR12 rates
• LDV/SOF STR safe and well-tolerated

52. Major HCV Headlines
• Interferon-free 3 DAA (ABT-45-/r/Ombitasvir)
Plus Ribavirin Regimen in HCV Genotype 1-
Infected Patients on Methadone or
Buprenorphine Achieved SVR24 of 97.4% (naïve
and experienced)
• Hepatic Safety Comparable for DTG to other HIV
therapy in INI-naïve Patients– Experienced may
be at Greater Risk for Viral Hepatitis-related IRIS
• FIB-4 Predicts Major Liver Complications and
Death in HCV+ People Starting ART

53. PrEP

54. Early Data Show Good Adherence to Intermittent
PrEP by MSM in French Trial (Ipergay)
• Potential benefits of iPrEP
– Higher adherence: more convenient dosing
regimen
– Improved efficacy
• Coitally-dependent use of TDF gel effect in CAPRISA 004
but daily TDF gel ineffective in VOICE
– Better safety: lower drug exposure (kidneys,
bones)
– More cost-effective

59. Conclusions
• First analysis of adherence showed a very high
detection rate of TFV and FTC in plasma with
“on demand” PrEP
• Results are encouraging but not
demonstration of efficacy
• Second phase of study to be implemented

60. Uptake of pre-exposure prophylaxis, sexual practices, and
HIV incidence in men and transgender women who have
sex with men: a cohort study (iPrEX OLE)
• iPrEx was first placebo-controlled trial to show that
daily TDF/FTC PrEP lowers the risk of HIV acquisition
• Analyzed MSM and transgender women who entered
the open-label extension, iPrEx OLE.
– PrEP could be started at any time through week 48, and
follow-up of all participants continued to week 72.
• Among 1770 people who enrolled at 11 sites in North
and South America, South Africa, and Thailand, 1603
eligible for PrEP.
– 72% started PrEP at enrollment, 6% started PrEP later, and
23% never started PrEP (n=1225 on PrEP)

65. Conclusions
• PrEP uptake is high across broad range of demographic groups
when provided free of charge by experienced PrEP providers
• Sexual risk a/w
– Higher retention between randomized phase and OLE
– Greater PrEP uptake
– Greater adherence
• ***Adherence has to be good, not perfect***
– Risk reduction 84% (95% CI: 21 to 99%) with 2-3 tabs/wk
– Risk reduction 100% (95% CI: 86-100%) with >3 tabs/wk
• PrEP fails if people stop while still at risk for HIV
• TVF-DP concentrations in DBS are convenient markers of long term
average PrEP use that correlate strongly with PrEP protection

66. Medical Male Circumcision
• A sport-based intervention to increase uptake of voluntary medical male
circumcision among adult male football players: results from a cluster-
randomised trial in Bulawayo, Zimbabwe
– "Make the Cut" intervention
– “Cluster randomized trial” of 3 arms found that VMMC uptake after 3 months
were 9.8-fold higher in the two intervention groups compared to the control
group.
• The effect of conditional economic compensation on uptake of voluntary
medical male circumcision: a randomized controlled trial of a demand
creation intervention for male circumcision in Kenya
– RCT of 1504 men
– Increasing levels of food voucher economic compensation (no
compensation, US $2.50, US $8.75, US $15.00) resulted in higher levels of
VMMC uptake.
– Despite statistically significant increases in uptake, uptake was profoundly
low ?level of compensation to achieve higher levels should be increased