Transcript Microbicides 2008 - Microbicide Trials Network

Overview of Tenofovir’s
Anticipated Adverse Events
and Resistance Concerns
Devika Singh, MD, MPH
Protocol Safety Physician
VOICE Training
July 2010
Today’s Discussion

How does tenofovir work against HIV?

What human body systems does it affect?

What adverse events can we anticipate
when tenofovir is used?
HIV Life Cycle
How does HIV enter the cell, and copy itself?
How do drugs exploit this process?
Key Concepts: Anti-retroviral (ARV)




ARVs are drugs to treat HIV designed to interfere with virus’s ability
to replicate
They are best used in combination,
i.e., anti-retroviral therapy (ART)
Different ARVs target different steps in
the HIV life cycle
Generally, ARVs are safe and effective
Approved Antiretrovirals (ARVs)
Nucleoside / tide reverse
transcriptase inhibitors:
 Zidovudine
 Didanosine
 Zalcitabine
 Stavudine
 Lamivudine
 Abacavir
Emtricitabine
 Tenofovir

Non-nucleoside reverse
transcriptase inhibitors:
 Delavirdine
 Nevirapine
 Efavirenz
 Etravirine
These drugs were approved in 2007/2008
Protease inhibitors:
•
•
•
•
•
•
•
•
•
•
Indinavir
Saquinavir
Nelfinavir
Amprenavir
Fosamprenavir
Lopinavir
Atazanavir
Darunavir
Tipranavir
Ritonavir
Fusion / Co-receptor inhibitors:
•
•
Enfuvirtide
Maraviroc
Integrase Inhibitors:
•
Raltegravir
2 keys are needed to “open the door”
 CD4 & chemokine receptors are required for viral entry
Fusion /
Entry
Inhibitors
Viral RNA is released (yellow strands)
Reverse transcription occurs
Genetic data is copied backwards from viral RNA to DNA
(Viral RNA yellow, DNA blue)
Reverse transcriptase inhibitors
Work by blocking this process
www.cellsalive.com
Tenofovir

Nucleoside reverse transcriptase inhibitor
(NRTI) drug used to treat HIV-1 infection in
adults

Interferes with HIV’s ability to reproduce itself by
inhibiting reverse transcriptase
Fusion /
Entry
Inhibitors
Reverse
Transcriptase
Inhibitors
Fusion /
Entry
Inhibitors
Reverse
Transcriptase
Inhibitors
Fusion /
Entry
Inhibitors
Reverse
Transcriptase
Inhibitors
Integrase Inhibitors
Viral DNA integrates into the host chromosome DNA
www.cellsalive.com
HIV uses the CD4 cell as a virus producing machine
 Cell operates like a photocopier
 Viral RNA coming off the photocopy is packaged in an `envelope`
 Eventually runs out of toner
www.cellsalive.com
Viral Protease is an enzyme that cuts up proteins
 These new virions are now mature
www.cellsalive.com
Protease inhibitors (PIs) block protease and
inhibit replication
www.cellsalive.com
Fusion /
Entry
Inhibitors
Protease Inhibitors
Reverse
Transcriptase
Inhibitors
Integrase Inhibitors
Release of new HIV virions
 Mature virions are now available to infect new
CD4 cells. This is how CD4 cells are profoundly
depleted as HIV infection progresses
Tenofovir

Dose: one 300 mg tablet taken once a day, with or
without food

Used in combination with other oral drugs

Safety profile comparable to placebo

Resistance emerges slowly
Also called Viread® or TDF
Truvada

Combination drug - tenofovir and emtricitabine
(FTC)

Both are NRTI’s

One tablet contains 200 mg of FTC and 300 mg
tenofovir taken once a day

Safety profile similar to tenofovir
Also called Truvada®, FTC/TDF or
tenofovir+FTC
Oral Tenofovir: How It’s Handled
Oral bioavailability ~25%
 After taking 300 mg orally, maximum
serum concentrations are achieved in
about 1 hour (+/- 0.4 hours)
 Half-life is 17 hours; persists in peripheral
blood cells much (PBMC) longer
 Must be taken up by cells to be activated

Tenofovir Diphosphate
Cellular
kinase
Tenofovir
(TDF; inactive)
Cellular
kinase
Tenofovir monophosphate
(inactive)
Tenofovir diphosphate
(active)
Intracellular
Extracellular
TDP: tenofovir diphosphate is active form; 2 phosphates added inside cells
TDF: tenofovir disoproxil fumarate; Inactive prodrug;
only active after modification inside cells
Potential adverse effects/events
What body systems does tenofovir affect?
Kidney
Bone
Liver
Adverse Events That May Lead to Product Hold




Hypophosphatemia
Decreased creatinine clearance
Nausea
Dipstick abnormalities
Clinical experience with Tenofovir:
>12,000 in expanded access programs
Clinical Trial Experience

3 large published clinical trials in HIV+; N = 1,544
(Gilead 903, 934, 907)

Incidence >10%, Grades 2-4






Rash
Diarrhea
Headache
Pain
Depression
Nausea
Oral Tenofovir: Elimination

Tenofovir is eliminated by the kidney at
two sites and using two mechanisms
Glomerular filtration
 Active tubular secretion

The Nephron, Basic Unit of the Kidney

Glucose, water, salts &
small metabolites are
filtered through
glomerulus & pass
through to tubule


Reabsorbed there
Protein is filtered at
glomerulus (kept in
blood)
TDF effect on kidney function
• Can affect the proximal
tubule
• Accumulates in the
proximal tubule
• “Spilling” of glucose
and phosphate in urine
(glucosuria,
hypophosphatemia)
TDF effect on kidney function
• Can also affect the
glomerulus, making it
“leaky”
• Protein in urine
• Lowered creatinine
clearance
• Elevated serum
creatinine
TDF effect on kidney function
• Accumulates in the proximal tubule
• “Spilling” of glucose and
phosphate in urine (glucosuria,
hypophosphatemia)
• Can also affect the glomerulus
• Protein in urine
• Lowered creatinine clearance
(creatinine, CrCl and
proteinuria)
• Tubular effects more common
(cohort studies suggest ~2%
incidence)
• Also a small, stable increase in
creatinine
Summary

Tenofovir accumulates in the proximal tubule
cells and can be toxic



Causes “spilling” of glucose and phosphate in urine
Look for glucosuria and hypophosphatemia in VOICE
Tenofovir can also affect the glomerulus


Protein in urine is due to damage at glomerulus
Why we look for changes in creatinine and proteinuria
in VOICE
Tenofovir Kidney Toxicity: Summary

Cohort studies suggest ~2% incidence of tubule
problems in HIV patients treated with TDF


Small, stable increase in creatinine
Normal renal response to acidemia is to
reabsorb all of the filtered bicarbonate and to
increase hydrogen excretion primarily by
enhancing the excretion of ammonium ions in
the urine

Impairment of this can lead to renal tubular acidosis
(RTA)
Tenofovir effect on liver


 Liver enzymes (AST, ALT) =
hepatitis
Lactic Acidosis / Severe
Hepatomegaly with steatosis
(fatty infiltration of liver)





Can occur with tenofovir use alone
or in combination anti-HIV therapy
May not have increases in liver
enzymes (transaminitis)
Majority of cases in women
Obesity and prolonged concomitant
nucleoside use may be risks
Pre-existing liver disease not
necessary
Tenofovir & Hepatitis B


Tenofovir is a treatment for hepatitis B infection
Worsening of chronic hepatitis B has been observed
after stopping tenofovir abruptly



Black box warning in package insert
Flares typically self-limited, but some reports of
more serious liver damage
For this reason, VOICE will exclude women with
chronic hepatitis B (HBSAg+) and encourage
immunization for women vulnerable
to future infection
Tenofovir: Post-Marketing Experience









Renal insufficiency, renal failure, acute renal failure, Fanconi
syndrome, proximal tubule problems, protein loss in urine,
increased creatinine, acute tubular necrosis (severe damage),
nephrogenic DI (diabetes insipidus), polyuria, interstitial nephritis
 liver enzymes (AST, ALT) --> hepatitis
Hypophosphatemia, lactic acidosis
Myopathy, osteomalacia (both associated with proximal renal
tubulopathy)
Allergic reaction
Dyspnea
Abdominal pain,  amylase, pancreatitis
Rash
Asthenia
Tenofovir: Precautions

New onset or worsening renal impairment, including
acute renal failure & Fanconi syndrome



Assess creatinine clearance pre-initiation; dose
adjust if <50
Monitor creatinine clearance and phosphate in
patients at risk
Avoid drugs that might damage the kidneys
*Package insert
Tenofovir: Precautions

Decreases in bone mineral density in HIV+ persons



Consider monitoring if h/o pathologic fracture or osteopenia risk
Osteomalacia (softening of bones) can also result from Fanconi
syndrome (loss of important minerals from kidney tubule)
Lipodystrophy - redistribution/accumulation of body fat

No data on setting when tenofovir is used as the only anti-HIV
drug
*Package insert
Truvada: Anticipated AE’s

Essentially contained in information already
presented about Tenofovir information (and in
its drug description/package insert) EXCEPT
for:

Skin discoloration



Hyperpigmentation (darkening of skin) primarily on palms
and soles
Generally mild and asymptomatic
Implications for product hold?

None discontinued for this reason in clinical trials
Oral PrEP:One Completed Trial




West Africa Phase II PrEP Trial (FHI/BMGF) in
HIV-negative women (n=936) in Ghana,
Cameroon, Nigeria
RCT: daily TDF 300 mg and placebo
Conducted June 2004 - March 2006
No evidence of increased clinical or laboratory
adverse effects
Peterson L, et al. PLoS Clinical Trials 2007
Phosphate


In FHI PrEP study, one grade 3
hypophosphatemia was seen in 428 p-y followup (Peterson 2007)
Partners PrEP study & MTN001 to date:




Not uncommon
Several grade 2 and one grade 3 hypophosphatemia
Nearly all NOT found to be persistent with repeat
testing; phosphate levels may vary in normal,
healthy people
Few holds for phosphate abnormalities
Adverse Events That May Lead to Product Hold




Hypophosphatemia
Decreased creatinine clearance
Nausea
Dipstick abnormalities
1% Tenofovir Vaginal Gel




Active ingredient is tenofovir (also called PMPA)
Provided in pre-filled applicators (40 mg TFV in 4
ml)
Leads to low levels of drug in the blood

Most levels below 5 ng/mL

Detectable in 79% of HPTN059 participants
Low frequency of side effects
Tenofovir 1% Gel: Clinical Experience

HPTN 050: Phase I study with 14 days of
product exposure


Male tolerance study (CONRAD)


PMPA gel safe and acceptable in HIV-infected and
uninfected women (Mayer, AIDS 2006)
No complaints
HPTN 059: Expanded safety study of 200
HIV-uninfected women in India and US
(Hillier, Microbicides 2008, New Delhi)
HPTN-059 Lessons Learned




Safety: Daily or coitally dependent 1% tenofovir
gel no different from placebo
Adherence: Coitally dependent adherence
within 2 hours of sex: 80%; 83% of daily doses
reported used
PK: 79% of women reporting gel use in past 12
hours had low but detectable plasma tenofovir
supporting self reported adherence data
Acceptability: Daily and coital use highly
acceptable to women and they would use it if
found to be effective at preventing HIV
Key Concepts: Resistance
Definition: ability of a microorganism to
survive and multiply in the presence of
drugs that would normally kill or weaken it.

For HIV, drug resistance means the virus
is no longer sensitive to one or more ARV

HIV is “resistant” to a medicine if it keeps
reproducing even while a person is taking
that medicine
Key Concepts: Resistance
How does it happen?



The enzyme HIV needs to replicate
(reverse transcriptase) is error prone,
resulting in mistakes (mutations)
Some mutations make the virus not
sensitive to a drug
The drug-resistant virus can now replicate
and take over other drug-sensitive virus
Resistance

Resistance is common in HIV-infected people
being treated with ART


Where ART is widely used, 5-20% of new HIV
infections can involve drug-resistant virus
Can be managed when detected early
(suppressed by other ARV combinations)

However, treatment options may be limited for some
types of resistance
Will resistance be a problem?

We don’t know


Very little scientific or clinical information is
available about the nature or incidence of
resistance among those using ARV-based
microbicides or oral ARVs for prevention,
however
Limited modeling data suggest circulating
drug resistance in the community won’t limit
PrEP effectiveness (Van de Vijver, JID, 2009)
Resistance with PrEP?

Impact on future care for people infected while on
PrEP is unknown

FHI trial in 936 HIV-negative women in Ghana
(primarily), Cameroon and Nigeria with daily
tenofovir:
 Tenofovir safe – no serious side effects
 8 seroconversions occurred: 2 in the active arm
and 6 in placebo arm
 HIV infections too few to draw conclusions on
efficacy
Moving Forward



Resistance will be a risk
associated with being in a
study like VOICE
At the same time, much more
research is needed because
we know very little
The risks are not considered
high enough to think that PrEP
studies should not be done
Summary: Implications





Non-specific, generalized complaints occur
commonly with tenofovir
Most will not necessitate product hold
However, presentation of severe AEs (ARF,
lactic acidosis), require balance between high
index of suspicion for immediate laboratory
evaluation & prudent watchful waiting
Clinical judgment will be critical!
We are carefully monitoring for HIV resistance
and want to minimize use of study products in
established HIV infection
Acknowledgments


Jeanne M. Marrazzo
Jane E. Hitti
Questions?
Serologic markers of acute
hepatitis B with recovery
HBV detectable by PCR
Source: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/index.htm
Serologic diagnosis of chronic
hepatitis B
HBV detectable by PCR
Source http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/index.htm
Hepatitis B serology interpretation (Appendix IV of protocol)
Test
Result
Interpretation & Management
HBsAg
Negative
HBV
susceptible (offer vaccination)
Flag chart & set up vaccination tracking log
If declined, counsel about infection risk &
potential for flares if ppt becomes infected
Revisit need for vaccination regularly & test
annually, at PUEV & 6mths after PUEV (oral).
anti-HBs
Negative
HBsAg
Negative
anti-HBs
Positive
possibly due to prior infection or
vaccination
Flag chart as “HBV Immune”. No further
action needed
HBsAg
Positive
HBV
anti-HBs
Negative
“Immune”
infected. Not eligible if at screening.
If detected during follow up, permanently stop
product & refer for care (per local standard)
AST/ALT at 1,2, 3 months after initiation of
product hold (Section 7.6.2)
Timing matters

Resistant virus is overtaken by sensitive virus
within weeks of stopping ARVs


Monkey studies: virus initially transmitted is usually not
drug-resistant, but resistance is more likely with time if
the PrEP ARV is continued
Mothers who took single dose nevirapine for pMTCT
and developed nevirapine resistance: no decrease in
response to ARV treatment if initiated after 6 months
(Mashi Study)

For this reason, we are testing frequently for new
HIV infection, and stopping study product
immediately if it’s detected (or strongly
suspected)