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AIDS CLINICAL ROUNDS

International AIDS Conference 2014: A Moderately Rapid Review

Jill Blumenthal, MD AIDS Rounds

8/8/2014

Overview

• HIV • HCV • PrEP • Most Innovative Implementation

Strategies

HIV

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 regimenimproved 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

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

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

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

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

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

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.

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

HCV

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

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

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

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

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

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

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

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

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

PrEP

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

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

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)

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

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