Devika Singh, MD, MPH
Protocol Safety Physician
VOICE Training
July 2010

 How does tenofovir work against HIV?
 What human body systems does it affect?
 What adverse events can we anticipate when tenofovir is used?

How does HIV enter the cell, and copy itself?
How do drugs exploit this process?

Key Concepts: Anti-retroviral (ARV)
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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
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Lamivudine
Abacavir
 Emtricitabine
 Tenofovir
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Protease inhibitors:
Indinavir
Saquinavir
Nelfinavir
Amprenavir
Fosamprenavir
Lopinavir
Atazanavir
Darunavir
Tipranavir
Ritonavir
Non-nucleoside reverse transcriptase inhibitors:
 Delavirdine
 Nevirapine
 Efavirenz
 Etravirine
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Integrase Inhibitors:
Raltegravir
These drugs were approved in 2007/2008
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Fusion / Co-receptor inhibitors:
Enfuvirtide
Maraviroc

2 keys are needed to “open the door”
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CD4 & chemokine receptors are required for viral entry

Fusion /
Entry
Inhibitors

Viral RNA is released (yellow strands)

Genetic data is copied backwards from viral RNA to DNA
(Viral RNA yellow, DNA blue) www.cellsalive.com
Reverse transcriptase inhibitors
Work by blocking this process

 Nucleoside reverse transcriptase inhibitor
(NRTI) drug used to treat HIV-1 infection in adults
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Interferes with HIV’s ability to reproduce itself by inhibiting reverse transcriptase

Reverse
Transcriptase
Inhibitors
Fusion /
Entry
Inhibitors

Reverse
Transcriptase
Inhibitors
Fusion /
Entry
Inhibitors

Reverse
Transcriptase
Inhibitors
Fusion /
Entry
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

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

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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

 Combination drug - tenofovir and emtricitabine
(FTC)
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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 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

Cellular kinase
Cellular kinase
Tenofovir
(TDF; inactive)
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

What body systems does tenofovir affect?
Kidney Bone Liver

Adverse Events That May Lead to Product Hold
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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
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Rash
Diarrhea
Headache
Pain
Depression
Nausea

 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
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 Reabsorbed there
Protein is filtered at glomerulus (kept in blood)

• Can affect the proximal tubule
• Accumulates in the proximal tubule
• “Spilling” of glucose and phosphate in urine
(glucosuria, hypophosphatemia)

• Can also affect the glomerulus, making it
“leaky”
• Protein in urine
• Lowered creatinine clearance
• Elevated serum creatinine

• 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
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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)

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Liver enzymes (AST, ALT) = hepatitis
Lactic Acidosis / Severe
Hepatomegaly with steatosis
(fatty infiltration of liver)
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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

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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
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 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)
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Allergic reaction
Dyspnea
Abdominal pain,
 amylase, pancreatitis
Rash
Asthenia

 New onset or worsening renal impairment, including acute renal failure & Fanconi syndrome
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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

 Decreases in bone mineral density in HIV+ persons
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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

 Essentially contained in information already presented about Tenofovir information (and in its drug description/package insert) EXCEPT for:
 Skin discoloration
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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

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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

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In FHI PrEP study, one grade 3 hypophosphatemia was seen in 428 p-y followup (Peterson 2007)
Partners PrEP study & MTN001 to date:
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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
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Hypophosphatemia
Decreased creatinine clearance
Nausea
Dipstick abnormalities

1% Tenofovir Vaginal Gel
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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
 PMPA gel safe and acceptable in HIV-infected and uninfected women (Mayer, AIDS 2006)
 Male tolerance study (CONRAD)
 No complaints
 HPTN 059: Expanded safety study of 200
HIV-uninfected women in India and US
(Hillier, Microbicides 2008, New Delhi)

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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

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
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HIV is “resistant” to a medicine if it keeps reproducing even while a person is taking that medicine

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 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

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We don’t know
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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)

 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

 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

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 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

 Jeanne M. Marrazzo
 Jane E. Hitti

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)
HBsAg
Test anti-HBs
Result
Negative
Negative
Interpretation & Management
 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).
HBsAg anti-HBs
Negative
Positive
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“Immune” possibly due to prior infection or vaccination
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Flag chart as “HBV Immune”. No further action needed
HBsAg anti-HBs
Positive
Negative
 HBV 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)

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Resistant virus is overtaken by sensitive virus within weeks of stopping ARVs
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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)