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Clinical Update August 2015

"Just as another DAA for HCV nears market, a HIV/ HCV co-epidemic in rural Indiana reminds us we can’t let our guard down in public health”


Two sentinel studies were recently published in the New England Journal of Medicine: ALLY-2 by DL Wyles et al and ION-4 by S Naggie et al.  Both continued to show that SVR-sustained virologic response rates- were similar in those with and without HIV in addition to their HCV. Attaining sustained virologic response (SVR) equates with virologic cure and is defined as an undetectable viral load 12 weeks after the cessation of therapy.

ALLY-2 was an open-label trial of 151 HCV treatment naïve and 52 treatment experienced patients. Naïve patients were randomized in a 2:1 fashion to 12 or 8 weeks of the NS5A inhibitor daclatasvir at a standard dose of 60 mg per day with dose adjustment for concomitant anti-retroviral therapy as needed. All patients received the nucleotide polymerase inhibitor sofosbuvir at 400 mg once-daily. Treatment experienced patients all received 12 weeks of therapy at the same doses. The primary endpoint was SVR at 12 week post-treatment in the HCV genotype 1 treatment naïve patients. 87% were male, 83% GT 1, 34% black, and 14% cirrhotic. 

Patients on ART had to have a VL<50 copies/ mL and CD4+ count of 100 cells/ microL. ARTs allowed in study patients were the ritonavir boosted protease inhibitors lopinavir, darunavir and atazanavir; the non-nucleoside reverse transcriptase inhibitors nevirapine, efavirenz and rilpivirine; the integrase inhibitors raltegravir and dolutegravir; the nucleoside/ nucleotide reverse transcriptase inhibitors tenofovir, abacavir, emtricitabine, lamivudine, and zidovudine; the fusion inhibitor enfuvirtide; and the entry inhibitor maraviroc. Those not on ART had to have a CD4+ count of at least 350 cells/ microL. Cirrhosis was determined by appropriate results via liver biopsy, FibroScan or FibroTest.

HCV genotypes 1-4 were enrolled with 83% having GT 1.  14% were compensated cirrhotics and 98% were on antiretroviral therapy.

ALLY-2

12 week treatment arm-

SVR by percentage

(95% confidence interval)

8 week treatment arm-

SVR by percentage

(95% confidence interval)

Genotype 1- Naive

96.4% (89.8-99.2)

75.6% (59.7-87.6)

Genotype 1- Treatment experienced

97.7% (88.0-99.9)

N/A

All genotypes-Naive

97.0% (91.6-99.4)

76.0% (61.8-86.9)

All Genotypes- Treatment experienced

98.1% (89.7-100)

N/A


The most commonly reported adverse effects were fatigue (17%), nausea (13%), and headache (11%) with no study drug discontinuations due to adverse events.
Declines in HCV viral load were rapid with 92-98% of patients at < 25 IU per mL by week 4 of treatment. No effect on HIV-1 suppression or CD4 count was noted.


On treatment HCV responses were similar in the 8 and 12 week groups, but relapse was more common after 8 weeks of treatment.  9 of the 12 with HCV relapses (7 of 10 in the 8 week group) received concurrent darunavir-ritonavir with daclatasvir at a reduced 30 mg dose. More recent data suggests the 60 mg dose would have been ideal with darunavir or lopinavir. The researchers also suggest that HIV-1 itself may adversely affect outcomes with the truncated course of therapy and recommend further research along these lines. Findings from this study suggest 12 weeks of therapy should be considered for all HIV-HCV co-infected patients.


In summary:

1.)    Daclatasvir plus sofosbuvir for 12 weeks resulted in high rates of SVR in GT 1 through 4 HCV in HIV co-infected persons, regardless of past HCV treatment, cirrhosis, or demographic or disease characteristics including black race.

2.)    The rate of SVR in the 8 week group was lower overall and across subgroups with the exception of those with a baseline VL of <2 million IU per mL (100%) as compared with a level of 2 million or greater IU per mL (62%).

3.)    HIV therapy including the majority of agents recommended by DHHS treatment guidelines were studied with no change in efficacy rates in the 12 week arms.

4.)    Lower efficacy after 8 weeks may be related to dose reduction in darunavir treated patients or other interplay with HIV infection itself so for now 12 weeks is the recommended regimen for the majority of HIV-HCV infected persons.




ION-4 was a multi-center, single-group, open-label trial of 335 HIV/HCV co-infected patients
.  75% were infected with GT 1a, 23% GT 1b, and 2% GT 4. 82% were male, 34% black, 20% compensated cirrhotics, and 55% had failed past HCV treatment (with 36% of this group having received direct acting antivirals).  Patients had to have been stable on ART for 8 weeks prior to screening with a VL<50 copies/ mL and CD4+ count of 100 cells/ microL. A minimum creatinine clearance of 60 mL/ min was required for enrollment. Based on drug-drug interaction data available at the beginning of the trial, ARTs allowed in study patients were tenofovir plus emtricitabine with efavirenz, rilpivirine or raltegravir. Cirrhosis was determined by appropriate results via liver biopsy, FibroScan or FibroTest.  Those with a history of alcohol or drug use within the past 12 months were excluded.

All patients received a fixed-dose combination tablet of the NS5A inhibitor ledipasvir 90 mg/ sofosbuvir 400 mg given once a day for 12 weeks. The primary endpoint was SVR at 12 week post-treatment with SVR of 24 weeks as the secondary endpoint.  

ION-4

Percentage Achieving SVR (95% Confidence Interval)

Overall

96%  (93-98)

GT 1a

96%  (93-98)

GT 1b

96%  (89-99)

GT 4

100%  (63-100)

 

No difference in rates of response at week 12 of treatment was seen with genotypes 1a versus 1b, by sex, by treatment history, by concomitant ART, or by cirrhosis status.

Thirteen patients (4%) did not achieve SVR. One person died at week 4 of treatment, 2 had breakthrough on treatment felt likely related to poor adherence, and 10 relapsed after treatment. All 10 relapsers were black with 7 having the TT allele in the gene encoding IL28B (which confers an increased risk of failure with interferon containing regimens). Black race and the TT allele in univariate analysis and black race alone in the multivariate were significant. The association of lower SVR with black race which comprised 34% of the study population was not seen in the studies of ledipasvir-sofosbuvir in HCV mono-infected persons and was not related to the CYP2B6 polymorphism which is more common in blacks and results in increased efavirenz levels.

Ledipasvir-sofosbuvir increases exposure to tenofovir by approximately 40%. Patients on ritonavir containing regimens may experience a relative increase of 30-60% in tenofovir exposure and so were excluded from the trial along with those on cobicistat containing combinations.


While 77% had an adverse event, they were usually mild-moderate and resulted in no premature study discontinuations. Headache (25%), fatigue (21%), and diarrhea (11%) were the most common adverse events. Eight patients suffered 15 serious adverse events with hepatocellular carcinoma in 2 and portal vein thrombosis in 2, all being reported in cirrhotics. Three patients suffered serious infections: sepsis, SBP and a respiratory infection followed by C. difficile colitis. Grade 3 lab abnormalities occurred in 9% and grade 4 in 2% with elevations in lipase, CPK, and serum glucose being most common. Both CD4 counts and HIV viral loads were stable throughout the study.


In summary:

1.)    Ledipasvir plus sofosbuvir for 12 weeks resulted in high rates of SVR in GT 1 or 4 HCV in HIV co-infected persons, regardless of past HCV treatment (including regimens with DAAs) or cirrhosis.

2.)    Response rates were similar to those seen with HCV mono-infection.

3.)    Ten patients, all black, relapsed after treatment with black race alone in multivariate analysis showing a significant association with relapse.

 

 

Daclatasvir is on its way with FDA approved expected 8/10/15

 

 

Drug-drug interactions may affect dosing of this compound.  Per the UK product insert, Daclatasvir is a substrate of both CYP3A4 and P-gP.

1.)    Strong or moderate inducers of CYP3A4 and P-gP may decrease plasma levels and therapeutic effect of daclatasvir so co-administration with strong inducers is contraindicated while administration with moderate inducers requires dose adjustment.

2.)    Strong inhibitors of CYP3A4 may increase plasma daclatasvir levels so dose adjustment of daclatasvir is needed. 

3.)    Co-administration with inhibitors of P-gP is likely to have a limited effects on daclatasvir exposure.

Antivirals, HIV or HBV

Mechanism

Daclatasvir Dosage 

(usual 60 mg/ day)

Protease Inhibitors

 

 

Atazanavir 300 mg / rtv 100 mg

Strong CYP3A4 inhibition

Decrease to 30 mg/ day

Darunavir or lopinavir with rtv

Not studied but expect strong CYP3A4 inhibition by PIs

Usage not recommended as insufficient data

Nucleoside/nucleotide reverse transcriptase inhibitors

 

 

Tenofovir disoproxil fumarate 300 mg/ day

No significant effects

No dose adjustment of either drug needed

3TC/FTC/AZT/DDI/D4T/ Abacavir

No significant effects

No dose adjustment of daclatasvir or NRTI needed

Non-nucleoside reverse transcriptase inhibitors

 

 

Efavirenz 600 mg / day

Induction of CYP3A4 by EFV

Increase to 90 mg/ day

Etravirine or nevirapine

Interaction not studied but expect CYP3A4 induction by NNRTI

Usage not recommended as insufficient data

Rilpivirine

Interaction not studied but no effect expected

No dose adjustment of either drug needed

Integrase inhibitors

 

 

Dolutegravir 50 mg/ day

Dolutegravir has no effect on daclatasvir with inhibition of P-gp and BCRP by daclatasvir increasing dolutegravir levels

No dose adjustment of either drug needed

Raltegravir

Interaction not studied but no effect expected

No dose adjustment of either drug needed

Fusion inhibitors

 

 

Enfuvirtide

Interaction not studied but no effect expected

No dose adjustment of either drug needed

CCR5 receptor antagonist

 

 

Maravroc

Interaction not studied but no effect expected

No dose adjustment of either drug needed

Pharmacokinetic enhancer

 

 

Cobicistat

Interaction not studied but strong CYP3A4 inhibition by cobicistat expected to increase daclatasvir

Decrease to 30 mg/ day

 

Other drug-drug interaction highlights from the UK label:

Drug Class

Dosage Recommendations for Co-administration

GI drugs

No dosage adjustment with famotidine or omeprazole.

 

Antibiotics

Reduce daclatasvir to 30 mg/ day with clarithromycin or telithromycin, but NO dose adjustment needed for azithromycin or ciprofloxacin.

 

Antifungals

No dose adjustment with fluconazole but decrease to 30 mg if used with ketoconazole, itraconazole, posaconazole or voriconazole.

 

Antimycobacterials

Don’t coadminister daclatasvir with rifampicin, rifabutin or rifapentine.

 

Anticoagulants

No dose adjustment with warfarin but while dabigatran hasn’t been studied, some increase in level expected so close monitoring advised with concomitant usage.

 

Anticonvulsants

Don’t co-administer daclatasvir with carbamazepine, oxcarbazepine, phenobarbital or phenytoin.

 

Immunosuppresants

No dose adjustment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil.

Narcotics

No dose adjustment with buprenorphine/ naloxone or methadone.

Lipid Lowering Agents

Use caution with rosuvastatin or other substrates of OATP 1B1 or BCRP (such as atorvastatin) as statin concentration may be increased.

Hormonal Contraceptives

No dose adjustment with oral contraceptive containing ethinylestradiol and norgestimate.

 

 

 

 

Rural Indiana HIV Outbreak Reminds Us of the Ongoing Risk Posed by Shared Needles and the Prescription Narcotic Epidemic in the US

A recent community outbreak of HIV infection linked to injection drug use of oxymorphone occurred in Indiana and was reported by C. Conrad et al. in the May 1, 2015 edition of the MMWR. The Indiana State Department of Health (ISDH) began an ongoing investigation of an HIV outbreak January 23, 2015 after disease intervention specialists in the state reported 11 confirmed cases of HIV traced to a rural southeastern Indiana county. Prior to this investigation only 5 HIV cases per year were reported in this county.

As of April 21, 135 persons had confirmed or probable HIV in a community of 4,200 persons. Mean age was 35 (range 18-57 years) and 54.8% were male. A small number of cases were in pregnant women who were placed on ART with no positive infants as of April 21. 80% reported IDU and 17% had not yet been interviewed. Amongst the 108 reporting IDU, all reported their drug of choice was injectable crushed oxymorphone, sometimes with other illicit drugs. 7.4% were female commercial sex workers. Strikingly, coinfection with HCV was found in 84.4% of patients.

Those interviewed reported an average of 9 syringe-sharing or sex partners and social contacts who may be at risk. Of the 230 contacts tested, 109 (47.4%) were positive for HIV. IDU in this community is multi-generational with the crushed oxymorphone (40 mg tablets are not designed to resist crushing) dissolved in non-sterile water and injected via insulin syringes with the syringed often shared. At 4 to 15 reported injections per day with 1 to 6 injection partners per event, the risk for both HIV and HCV is alarmingly high.

Rife with unemployment, poverty, lack of education and limited access to health care, this county is similar to many rural US counties with this outbreak highlighting the need for community interventions at multiple levels through the CDC, academic partners, and state and local health departments. It also highlights the vulnerability of many resource poor rural communities which traditionally have low rates of HIV and HCV and reminds us how often concomitant transmission of the 2 viruses continues to occur, particularly in vulnerable IDU and MSM populations.

 


 

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