table f-6 pharmacokinetic interactions between
table f-5 dose adjustments for

| Concomitant Medication                                                                                                                                                                     | Voriconazole Effect [24,25]             | Mechanism                                                           | Recommendation                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|---------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Calcineurin Inhibitors - Tacrolimus - Cyclosporine                                                                                                                                         | ↑↑ Calcineurin Levels                   | Moderate inhibition of                                              | Upon initiation of voriconazole:                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| CYP3A4                                                                                                                                                                                     | -                                       | Decrease tacrolimus daily dose by 67%                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| -                                                                                                                                                                                          | Decrease cyclosporine daily dose by 50% |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Monitor daily trough levels of the calcineurin inhibitors and  adjust doses as needed.                                                                                                     |                                         |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| mTOR Inhibitors                                                                                                                                                                            | ↑↑↑ Sirolimus Levels                    | Moderate inhibition of                                              | Voriconazole should not be used unless deemed absolutely                                                                                                                                                                                                                                                                                                                                                                                                                    |
| -                                                                                                                                                                                          | Sirolimus                               | CYP3A4                                                              | clinically necessary. If voriconazole must be added to control  fungal infection, then following the 90% reduction in sirolimus  dosing serum levels should be measured 24-48 hours later and  then every 3-4 days until levels are stable and in the desired  range. If voriconazole is given intravenously, or if voriconazole  and sirolimus are not given together, these guidelines may not  apply because the effect on bioavailability of sirolimus will be  weaker. |
| Antimetabolites                                                                                                                                                                            | None                                    | N/A                                                                 | No adjustments necessary.                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| -                                                                                                                                                                                          | Mycophenolate mofetil                   |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Alkylating Agents                                                                                                                                                                          | ↑↑ Cyclophosphamide and 4-              | Moderate inhibition of                                              | Concomitant use is discouraged due to the accumulation of the                                                                                                                                                                                                                                                                                                                                                                                                               |
| hydroxycyclophosphamide                                                                                                                                                                    | CYP3A4 and 2C19                         | toxic metabolite 4-hydroxycyclophosphamide28                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| -                                                                                                                                                                                          | Cyclophosphamide                        |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Protease Inhibitors                                                                                                                                                                        | ↓↓↓ Voriconazole                        | Strong induction of                                                 | Contraindicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| -                                                                                                                                                                                          | Ritonavir (400mg BID)                   | (Decreased by 66 - 80%)                                             | CYP2C9 and 2C19                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Protease Inhibitors (boosted) - Fosamprenavir/ritonavir (fAPV/r) - Indinavir/ritonavir (IND/r) - Lopinavir/ritonavir (LPV/r) - Saquinavir/ritonavir (SQV/r) - Tipranavir/ritonavir (TPV/r) | ↓↓ Voriconazole                         | Strong induction of                                                 | Avoid concomitant use whenever possible.                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| (Decreased by 24 - 40%)                                                                                                                                                                    | CYP2C9 and CYP2C19                      | Monitor voriconazole trough levels bi-weekly and adjust as  needed. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| F-17                                                                                                                                                                                       |                                         |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
| Concomitant Medication                                                                                                                         | Voriconazole Effect [24,25]                                                                        | Mechanism                                               | Recommendation                                 |                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|---------------------------------------------------------|------------------------------------------------|---------------------------------------------------------------------|
| Protease Inhibitors (unboosted) - Amprenavir (AMP) - Atazanavir (ATZ) - Indivavir (IDV) - Nelfinavir (NFV) - Saquinavir (SQV)                  | ↑ Protease Inhibitor Level                                                                         | Weak inhibition of                                      | Frequent monitoring of adverse effects.        |                                                                     |
| CYP3A4                                                                                                                                         |                                                                                                    |                                                         |                                                |                                                                     |
| NNRTIs                                                                                                                                         | ↓ Voriconazole                                                                                     |                                                         |                                                |                                                                     |
| -                                                                                                                                              | Efavirenz (EFV)                                                                                    | (Decrease AUC by 77%) ↑ Efavirenz (Increase AUC by 44%) | Two way interaction                            | Increase voriconazole dose to 400 mg twice daily and decrease       |
| via CYP3A4                                                                                                                                     | efavirenz dose to 300mg daily. Monitor voriconazole trough levels bi-weekly and adjust as  needed. |                                                         |                                                |                                                                     |
| NNRTIs                                                                                                                                         | ↑ Voriconazole (possible)                                                                          | Two way interaction                                     | Frequent monitoring of adverse effects.        |                                                                     |
| -                                                                                                                                              | Etravirine (ETV)                                                                                   | ↑ Etravirine (possible)                                 | via CYP3A4                                     | Monitor voriconazole trough levels bi-weekly and adjust as  needed. |
| NNRTIs                                                                                                                                         | ↓ Voriconazole (possible)                                                                          | Two way interaction                                     | Frequent monitoring of adverse effects.        |                                                                     |
| -                                                                                                                                              | Nevirapine (NVP)                                                                                   | ↑ Nevirapine (possible)                                 | via CYP3A4                                     | Monitor voriconazole trough levels bi-weekly and adjust as  needed. |
| NRTIs - Abacavir (ABC) - Didanosine (ddI) - Emtricitabine (FTC) - Lamivudine (3TC) - Stavudine (d4T) - Tenofovir (TDF) - Zidovudine (AZT, ZDV) | None                                                                                               | N/A                                                     | No adjustments necessary.                      |                                                                     |
| Integrase Inhibitor                                                                                                                            | None                                                                                               | N/A                                                     | No adjustments necessary.                      |                                                                     |
| -                                                                                                                                              | Raltegravir (RLV)                                                                                  | Raltegravir based regimens may be preferred over PI- or NNRTIbased regimens as it is primarily metabolized via glucuronidation  and not by CYP3A4.                                                         |                                                |                                                                     |
| Fusion Inhibitor                                                                                                                               | None                                                                                               | N/A                                                     | No adjustments necessary.                      |                                                                     |
| -                                                                                                                                              | Enfuviritide (ENF, T20)                                                                            |                                                         |                                                |                                                                     |
| CCR5 Antagonist                                                                                                                                | ↑ Maraviroc Levels                                                                                 | N/A                                                     | Decreased maraviroc dose to 150 mg twice daily |                                                                     |
| -                                                                                                                                              | Maraviroc (MVC)                                                                                    |                                                         |                                                |                                                                     |  
II. **Posaconazole**
a. Standard Dose i. PO: 200 mg three times a day (5 mL of oral suspension given with a high-fat meal)
b. Target Trough Level i. ≥ 0.5 µg/mL  
| Concomitant Medication                                                                                                                                                                     | Posaconazole Effect [24,26]                                                                                                                    | Mechanism                             | Recommendation                                                                                                                                     |                                              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------|
| Calcineurin Inhibitors - Tacrolimus - Cyclosporine                                                                                                                                         | ↑↑ Calcineurin Levels                                                                                                                          | Moderate inhibition of                | Upon initiation of posaconazole:                                                                                                                   |                                              |
| CYP3A4                                                                                                                                                                                     | -                                                                                                                                              | Decrease tacrolimus daily dose by 67% |                                                                                                                                                    |                                              |
| -                                                                                                                                                                                          | Decrease cyclosporine daily dose by 25%                                                                                                        |                                       |                                                                                                                                                    |                                              |
| Monitor daily trough levels of the calcineurin inhibitors and  adjust doses as needed.                                                                                                     |                                                                                                                                                |                                       |                                                                                                                                                    |                                              |
| mTOR Inhibitors                                                                                                                                                                            | ↑↑↑ Sirolimus Levels                                                                                                                           | Moderate inhibition of                | Contraindicated, use alternative antifungal therapy whenever                                                                                       |                                              |
| -                                                                                                                                                                                          | Sirolimus                                                                                                                                      | (Increase by 788%)                    | CYP3A4                                                                                                                                             | possible.                                    |
| Antimetabolites                                                                                                                                                                            | None                                                                                                                                           | N/A                                   | No adjustments necessary.                                                                                                                          |                                              |
| -                                                                                                                                                                                          | Mycophenolate mofetil                                                                                                                          |                                       |                                                                                                                                                    |                                              |
| Alkylating Agents                                                                                                                                                                          | ↑↑ Cyclophosphamide and 4-                                                                                                                     | Moderate inhibition of                | Concomitant use is discouraged due to the accumulation of the                                                                                      |                                              |
| -                                                                                                                                                                                          | Cyclophosphamide                                                                                                                               | hydroxycyclophosphamide               | CYP3A4                                                                                                                                             | toxic metabolite 4-hydroxycyclophosphamide28 |
| Protease Inhibitors (boosted) - Fosamprenavir/ritonavir (fAPV/r) - Indinavir/ritonavir (IND/r) - Lopinavir/ritonavir (LPV/r) - Saquinavir/ritonavir (SQV/r) - Tipranavir/ritonavir (TPV/r) | ↑ Protease Inhibitor Level                                                                                                                     | Weak inhibition of                    | Frequent monitoring of adverse effects.                                                                                                            | Consider alternative                         |
| CYP3A4                                                                                                                                                                                     | antifungal therapy. Monitor posaconazole trough levels bi-weekly and adjust as  needed. Dose of posaconazole may be decreased with high level. |                                       |                                                                                                                                                    |                                              |
| Protease Inhibitors (unboosted) - Amprenavir (AMP) - Atazanavir (ATZ) - Indivavir (IDV) - Nelfinavir (NFV) - Saquinavir (SQV)                                                              | ↑ Protease Inhibitor Level                                                                                                                     | Weak inhibition of                    | Frequent monitoring of adverse effects.                                                                                                            |                                              |
| CYP3A4                                                                                                                                                                                     | Atazanavir AUC increased by 268%.                                                                                                              |                                       |                                                                                                                                                    |                                              |
| NNRTIs                                                                                                                                                                                     | ↓ Posaconazole                                                                                                                                 | Strong induction of                   |                                                                                                                                                    |                                              |
| (Decrease AUC by 50%)                                                                                                                                                                      | CYP3A4 and UDP-G                                                                                                                               |                                       |                                                                                                                                                    |                                              |
| -                                                                                                                                                                                          | Efavirenz (EFV)                                                                                                                                | induction                             | Consider alternative antifungal therapy. Monitor posaconazole trough levels bi-weekly and adjust as  needed. Dose may be increased with low level. |                                              |
| F-19                                                                                                                                                                                       |                                                                                                                                                |                                       |                                                                                                                                                    |                                              |  
| Concomitant Medication                                                                                                                         | Posaconazole Effect [24,26]   | Mechanism               | Recommendation                          |                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|-------------------------|-----------------------------------------|---------------------------------------------------------------------|
| NNRTIs                                                                                                                                         | ↑ Etravirine (possible)       | Weak inhibition of      | No adjustments necessary.               |                                                                     |
| -                                                                                                                                              | Etravirine (ETV)              | CYP3A4                  |                                         |                                                                     |
| NNRTIs                                                                                                                                         | ↓ Posaconazole (possible)     | Two way interaction     | Frequent monitoring of adverse effects. |                                                                     |
| -                                                                                                                                              | Nevirapine (NVP)              | ↑ Nevirapine (possible) | via CYP3A4                              | Monitor Posaconazole trough levels bi-weekly and adjust as  needed. |
| NRTIs - Abacavir (ABC) - Didanosine (ddI) - Emtricitabine (FTC) - Lamivudine (3TC) - Stavudine (d4T) - Tenofovir (TDF) - Zidovudine (AZT, ZDV) | None                          | N/A                     | No adjustments necessary.               |                                                                     |
| Integrase Inhibitor                                                                                                                            | None                          | N/A                     | No adjustments necessary.               |                                                                     |
| -                                                                                                                                              | Raltegravir (RLV)             | Raltegravir based regimens may be preferred over PI- or NNRTIbased regimens as it is primarily metabolized via glucuronidation  and not by CYP3A4.                         |                                         |                                                                     |
| Fusion Inhibitor                                                                                                                               | None                          | N/A                     | No adjustments necessary.               |                                                                     |
| -                                                                                                                                              | Enfuvirtide (ENF, T20)        |                         |                                         |                                                                     |
| CCR5 Antagonist                                                                                                                                | None                          | N/A                     | No adjustments necessary.               |                                                                     |
| -                                                                                                                                              | Maraviroc (MVC)               |                         |                                         |                                                                     |
table f-6 pharmacokinetic interactions between
iii. fluconazole

a. Standard Dose i. IV: 200 - 400 mg daily (Convert to oral administration when patient is able to tolerate)
ii. PO: 200 - 400 mg daily  
| Concomitant Medication                                                                                                                                                                     | Fluconazole Effect [24,27]   | Mechanism             | Recommendation                                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|-----------------------|---------------------------------------------------------------|
| Calcineurin Inhibitors - Tacrolimus - Cyclosporine                                                                                                                                         | ↑ Calcineurin Levels         | Weak inhibition of    | Monitor daily trough levels of the calcineurin inhibitors and |
| CYP3A4                                                                                                                                                                                     | adjust doses as needed.      |                       |                                                               |
| mTOR Inhibitors                                                                                                                                                                            | ↑ Sirolimus Levels           | Weak inhibition of    | Monitor daily trough levels of the calcineurin inhibitors and |
| -                                                                                                                                                                                          | Sirolimus                    | CYP3A4                | adjust doses as needed.                                       |
| Antimetabolites                                                                                                                                                                            | None                         | N/A                   | No adjustments necessary.                                     |
| -                                                                                                                                                                                          | Mycophenolate mofetil        |                       |                                                               |
| Alkylating Agents                                                                                                                                                                          | Minimal effect on            | Minimal inhibition of | No adjustments necessary.28                                   |
| -                                                                                                                                                                                          | Cyclophosphamide             | cyclophosphamide      | 2C9                                                           |
| Protease Inhibitors (boosted) - Fosamprenavir/ritonavir (fAPV/r) - Indinavir/ritonavir (IND/r) - Lopinavir/ritonavir (LPV/r) - Saquinavir/ritonavir (SQV/r) - Tipranavir/ritonavir (TPV/r) | None                         | Weak inhibition of    | No adjustments necessary.                                     |
| ↑ Tipranavir Levels                                                                                                                                                                        | CYP3A4                       | Fluconazole doses > 200 mg are not recommended with coadministration of TPV/r.                       |                                                               |
| Protease Inhibitors (unboosted) - Amprenavir (AMP) - Atazanavir (ATZ) - Indivavir (IDV) - Nelfinavir (NFV) - Saquinavir (SQV)                                                              | None                         | N/A                   | No adjustments necessary.                                     |
| NNRTIs                                                                                                                                                                                     | None                         | N/A                   | No adjustments necessary.                                     |
| -                                                                                                                                                                                          | Efavirenz (EFV)              |                       |                                                               |
| NNRTIs                                                                                                                                                                                     | ↑ Etravirine (possible)      | N/A                   | No adjustments necessary.                                     |
| -                                                                                                                                                                                          | Etravirine (ETV)             | F-21                  |                                                               |  
| Concomitant Medication                                                                                                                         | Fluconazole Effect [24,27]   | Mechanism              | Recommendation                                                     |                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|------------------------|--------------------------------------------------------------------|-----------------------------------------|
| NNRTIs                                                                                                                                         | ↑ Nevirapine                 | Weak inhibition of     | Frequent monitoring of liver function tests as combination results |                                         |
| -                                                                                                                                              | Nevirapine (NVP)             | (Increase AUC by 110%) | CYP3A4                                                             | in an increased risk of hepatotoxicity. |
| NRTIs - Abacavir (ABC) - Didanosine (ddI) - Emtricitabine (FTC) - Lamivudine (3TC) - Stavudine (d4T) - Tenofovir (TDF) - Zidovudine (AZT, ZDV) | None                         | N/A                    | No adjustments necessary.                                          |                                         |
| Integrase Inhibitor                                                                                                                            | None                         | N/A                    | No adjustments necessary.                                          |                                         |
| -                                                                                                                                              | Raltegravir (RLV)            | Raltegravir based regimens may be preferred over PI- or NNRTIbased regimens as it is primarily metabolized via glucuronidation  and not by CYP3A4.                        |                                                                    |                                         |
| Fusion Inhibitor                                                                                                                               | None                         | N/A                    | No adjustments necessary.                                          |                                         |
| -                                                                                                                                              | Enfuvirtide (ENF, T20)       |                        |                                                                    |                                         |
| CCR5 Antagonist                                                                                                                                | None                         | N/A                    | No adjustments necessary.                                          |                                         |
| -                                                                                                                                              | Maraviroc (MVC)              |                        |                                                                    |                                         |  
IV. Echinocandin Agents (Anidulafungin, Micafungin, Caspofungin)
a. Drug Interactions i. Not metabolized through CYP co-enzymes. The potential for drug-drug interactions is low.
table f-6 pharmacokinetic interactions between
v. amphotericin b and derivatives

a. Drug Interactions i. Not metabolized through CYP co-enzymes. The potential for drug-drug interactions is low.
table f-6 pharmacokinetic interactions between
references

1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed (2 February 2010) [p. 130-140]
2. Vfend [package insert]. New York, NY: Pfizer Inc.; 2008. 3. Noxafil [package insert]. Kenilworth, NJ: Schering-Plough; 2008. 4. Diflucan [package insert]. New York, NY: Pfizer Inc.; 2008. 5. Marr KA, Leisenring W, Crippa F, et al. Cyclophosphamide metabolism is affected by azole antifungals. *Blood* 2004;103:1557-1559.
appendix g karnofsky and lansky
references

| Percentage 100   | Normal, no complaints, no evidence of disease                                 |
|------------------|-------------------------------------------------------------------------------|
| 90               | Able to carry on normal activity; minor signs or symptoms of disease          |
| 80               | Normal activity with effort; some signs or symptoms of disease                |
| 70               | Cares for self; unable to carry on normal activity or do active work          |
| 60               | Requires occasional assistance, but is able to care for most of his/her needs |
| 50               | Requires considerable assistance and frequent medical care                    |
| 40               | Disabled; requires special care and assistance                                |
| 30               | Severely disabled, hospitalization indicated. Death not imminent              |
| 20               | Very sick, hospitalization necessary, active supportive treatment necessary   |
| 10               | Moribund, fatal processes, progressing rapidly                                |
| 0                | Dead                                                                          |
appendix g karnofsky and lansky
karnofsky scale >= 16 years

| Percentage 100   | Fully Active                                                                             |
|------------------|------------------------------------------------------------------------------------------|
| 90               | Minor restriction in physically strenuous play                                           |
| 80               | Restricted in strenuous play, tires more easily, otherwise active                        |
| 70               | Both greater restrictions of, and less time spent in, active play                        |
| 60               | Ambulatory up to 50% of time, limited active play with assistance/supervision            |
| 50               | Considerable assistance required for any active play; fully able to engage in quiet play |
| 40               | Able to initiate quiet activities                                                        |
| 30               | Needs considerable assistance for quiet activity                                         |
| 20               | Limited to very passive activity initiated by others (e.g., TV)                          |
| 10               | Completely disabled, not even passive play                                               |
| 0                | Dead                                                                                     |
appendix g karnofsky and lansky
lansky scale < 16 years

Karnofsky DA: Meaningful clinical classification of therapeutic responses to anti-cancer drugs. Editorial: Clin Pharmacol Ther 2:709-712, 1961.
appendix h sequential probability ratio
i. background - the sequential

Let f x( ; ) be the density function for random variable X. According to the Neyman-Pearson theory, the most powerful test of H = o
:
0versus1 1 H : =decides in favor of H1 ifL c n  
and in favor of H0 if n  cL, respectively, where  ( ; ) / ( ; ) 1 0 n n i i i L f x f x =  is the likelihood ratio, and cis determined to have the size. When the sample size is not fixed in advance, further improvement is possible by using Wald's Sequential Probability Ratio Test (SPRT). The SPRT continues to sample as long as n  ALBfor some constant 1  AB, stops sampling and decides in favor of H1 as soon as n  AL, and stops sampling and decides in favor of H0 as soon as n  BL .  
The usual measures of performance of such a procedure are the error probabilities α andof rejecting H0 when= 0
, and of accepting H0 when= 1
, respectively, and the expected sample size*NENE* )()|(   jj
. Wald and Wolfowitz showed that among all tests, sequential or not, for which Pr0 H0
)reject ( and1 0 Pr (reject ) H  , and for which NE )(
jare finite, j=0, 1, the SPRT with error probabilities α and minimizes )(
0 NEand)(
1 NE. If, in addition, xx ,...2,1are independent and identically distributed (i.i.d.) with density functionxf  ),(, with monotone likelihood ratio in x)(, then any SPRT for testing  0 against 1 has non-decreasing power function. For the SPRT with error probabilities α and, the SPRT boundaries are given approximately by A −= /)1( and B /( −=  )1. The operating characteristics of the SPRT are given by  
```
)1(),,,,( /( )
)( )()(
10

h h h O A −−= BAwhere h  )(is the non-trivial solution to the equation
,(/);(( )) =1);(
)(
1 2xfxfxf dx h

.

```  
The formula *E N O A O B E z* ( ; ) 1 ( ) log ( )log / ( ; )    = − +   ( )
provides the average sample number for an arbitrary. The sample size distribution is very highly skewed,2
([)( *NENVar* )]. Thus we will consider a truncated test with maximum sample size of N0 and simulate to obtain the operating characteristics of the test.
appendix h sequential probability ratio
ii. sequential probability ratio test

The goal of the study is to assess feasibility and safety of allogeneic HCT in HIV-infected patients using 100-day NRM as the primary endpoint. To establish safety we want to show that 100-day NRM is lower than 45% with a targeted NRM probability of 15%. This is equivalent to testing H0: p ≥ 0.45 vs. Ha: p ≤ 0.15. To guard against excessive non-relapse mortality, we wish to construct stopping guidelines using the *futility boundary* of an SPRT test of H0: p = 0.45 vs. Ha: p = 0.15 with nominal Type I error α = .07 and Type II error β = .30. The stopping boundary is reached when NRM is high and it is no longer likely that we would be able to reject the null hypothesis at the end of the study. Otherwise, the trial will continue on.  
Let 1, 2, ⋯ ,  be the indicator of non-relapse mortality status at day 100 for patient i where
,  = 1, ⋯ , , are *i.i.d.* Bernoulli random variables with probability p. Let  = ∑  
=1 be the total number of non-relapse deaths observed by day 100, then X is a binomial random variable with probability mass function (; ) = (  
)
(1 − )
(−). The SPRT is derived based on a simple null and alternative hypothesis H0: p = p0 = 0.45 vs. Ha: p = p1 = 0.15 with α = .07 and β =
.30. Since the log-likelihood ratio for the binomial,
[(; 1)/(; 0
)] = [1/0
] + ( − )[(1 − 1)/(1 − 0)]
is a monotone function of x, the test has non-decreasing power function. Therefore, the SPRT is a one-sided level 0.07 test for a composite null hypothesis H0: p ≥ 0.45 versus a composite alternative hypothesis Ha: p ≤ 0.15 with power 1 - β = .70.  
In this study, stopping only occurs when non-relapse mortality is too high that it is unlikely that the null hypothesis would be rejected at full recruitment. The SPRT pauses when the likelihoodratio statistics,  
= (; 1) (; 0 ) = 1 (1 − 1) (−) 0 (1 − 0) (−) <  or equivalently,  log () =  ∗  ( 1 0 ) + ( − ) ∗  ( 1 − 1 1 − 0 ) <   ∗ ( ( 1 0 ) −  ( 1−1 1−0 )) <  −  ∗  ( 1−1 1−0 ). When 1 < 0, (1/0 ) − ((1 − 1 )/(1 − 0 )) < 0. The stopping region is defined by  > ( 1 0 )−( 1−1 1−0 ) −  ∗ ( 1−1 1−0 ) ( 1 0 )−( 1−1 1−0 ) = .738 + .283.
The SPRT can be represented graphically by plotting the number of non-relapse deaths by day 100 (x) versus the number of patients enrolled in the study (n). The stopping boundary is represented by the line with the slope equals to .283 and an intercept of .738. The stopping region is the area above the stopping boundary and the continuation region is the area below the boundary. See figure H.1.
appendix h sequential probability ratio
figure h.1 sprt stopping guidelines

The futility stopping guidelines derived from the SPRT are summarized in Table H.1.  
| Number of patients enrolled   | SPRT stopping boundary   |
|-------------------------------|--------------------------|
| (n)                           | (x)                      |
| 2-4                           | 2                        |
| 5-7                           | 3                        |
| 8-11                          | 4                        |
| 12-15                         | 5                        |  
The operating characteristics of the truncated SPRT with maximum sample size of 15 resulting from a simulation study with 10,000 replications are shown in Table H.2. The truncated SPRT test has Type I error of 8% and power of 83%.
appendix h sequential probability ratio
table h.2 operating characteristics for

| Non-relapse Mortality                           |      |      |      |      |
|-------------------------------------------------|------|------|------|------|
| True 100-day rate                               | 45%  | 35%  | 25%  | 15%  |
| Probability stop and accept the null hypothesis | .92  | .75  | .47  | .17  |
| Mean month stopped                              | 11.8 | 15.6 | 20.2 | 24.5 |
| Mean # endpoints                                | 2.7  | 2.9  | 2.8  | 2.0  |
| Mean patients with 100 days follow up           | 6.0  | 8.2  | 10.8 | 13.4 |
appendix i nmdp procedure for
background

A recent case report by Hütter et al. (NEJM, 2009) documented the outcome of an allogeneic hematopoietic cell transplant (HCT) performed for the treatment of acute myeloid leukemia (AML) in which the well-matched donor was selected for homozygosity for the CCR5delta32 mutation. The recipient had been known to be HIV-infected prior to developing AML and the German transplant team hypothesized that hematopoietic cells from such a donor could confer natural resistance to HIV infection in the transplanted hematopoietic and immune cells. A single HLA-matched donor homozygous for the CCR5delta32 mutation was identified among approximately 80 well-matched donors and an allogeneic HCT for the treatment of the patient's AML was performed using that donor. Following the transplant, the recipient's antiretroviral medications were discontinued and viral titers were monitored. No subsequent recrudescence of HIV replication was detected. The recipient relapsed with AML approximately one year later but a second HCT using the same donor was successfully performed with continued primary disease remission and HIV control with undetectable HIV viral loads two years following the second transplant (Hütter, personal communication). The of BMT CTN 0903 Protocol Team would like to replicate these findings in the context of allogeneic HCT as proposed under Protocol 0903. The enrollment for the study is 15 patients. It is known that the incidence of CCR5delta32 homozygosity is essentially limited to European populations, with highest incidence in Northern Europeans (Galvani and Novembre, 2005); from these data, it is apparent that non-European populations manifest homozygosity too rarely to warrant evaluation. Additionally, it is also known that donor ethnicity strongly correlates with recipient ethnicity. As a consequence, it is expected that only subject enrolled on 0903 who is of European descent will have a reasonable likelihood of a suitably HLA-matched donor who also has CCR5delta32 homozygosity. It is estimated that of the 15 patients to be enrolled on study, approximately 2/3 or 10 patients will be of European descent. Of those 10 patients, approximately 7 will not have a sibling match. The search for an HLA well-matched donor with homozygosity will therefore be limited to this population. In order to understand how many patients would be expected to have sufficient donors to have a chance of having a CCR5delta32 homozygous donor, 30 consecutive Caucasian patients searching for a suitably matched donor were assessed for availability of potential 5/6 or 6/6 donors at HLA-A, -B, and –DRB1 using HapLogic 2. In that study, 3 of 30 patients had more than 200 potentially matched donors. Another 6 of 30 had at least 20 but less than 100 donors. Thus, of the 15 patients to be studied on 0903, approximately 1 patient is likely to have a suitably matched CCR5delta32 homozygous donor. Two other patients have a smaller chance of identifying such a donor, so it is estimated that 1-2 patients will be able to undergo HCT with such a donor. It should be noted that the 0903 Protocol Team feels that a patient with multiple unrelated donors should be given the option to receive product from a well-matched unrelated donor even if a sibling donor is available as long as logistical and financial barriers for such an HCT can be managed.
appendix i nmdp procedure for
guiding principles for donor selection

1) The first priority for donor selection should be HLA matching such that an 8/8 nonhomozygous donor, including a sibling, for example, would be selected over a 7/8 CCR5delta32 homozygous donor.  
2) If a sibling donor and a well-matched CCR5delta32 homozygous donor are both available, then the transplant team and patient should decide together which donor is to be selected.
appendix i nmdp procedure for
for whom will an assessment

1) An attempt to identify a suitably HLA-matched donor with CCR5delta32 homozygosity for a patient screened and enrolled on 0903 will take place when the following minimum conditions are met:
a. There is a donor with at least a 50% chance of having a 5/6 match using HapLogic 2 or a 7/8 match (HLA-A, -B, -C, -DR) based on HapLogic 3 prediction when available 2) The assumption is that, in parallel with the search for a CCR5delta32 homozygous donor, the standard process for identifying a donor will be followed with typical NMDP and transplant center procedures (i.e. donors will be selected by HLA and non-HLA factors, other than CCR5delta32 mutation status).  
3) The identification of a suitable unrelated donor **must not be delayed** by the process to identify a donor who is CCR5delta32 homozygous.
appendix i nmdp procedure for
overview of the process for

1) When a preliminary search for a patient on 0903 meets the criteria above, potential donors as defined by the HapLogic search and the matching criteria above will be contacted by the NMDP Member Services Donor Contact Team to confirm continued interest and availability to serve as a donor. The Member Services Donor Contact Team will also inform the potential donor that there is a research protocol associated with donation and that the research component will be explained by the CIBMTR Survey Research Group in a separate conversation.  
2) For donors who are available and willing to donate, then the donor information will be passed to the CIBMTR Survey Research Group to inform the donor about BMT CTN 0903 and the goal of obtaining a CCR5 delta 32 homozygous donor. The donor will be asked to participate in CCR5delta32 screening and those who provide verbal agreement will be sent a buccal swab kit by mail with a consent form to sign and return and an instruction sheet with the swabs. The potential donor will return the buccal swab to the NMDP Sample Repository for logging and then batching to the CCR5 research testing laboratory. Donors will be informed that CCR5 testing is unlikely to reveal homozygosity and unless they are contacted specifically about homozygosity, then the result did not reveal homozygosity. If the donor is homozygous, s/he will be counseled about the significance of this finding, irrespective of whether that donor is ultimately chosen as the donor for an 0903 subject.  
3) The testing laboratory will provide results to the Protocol Officer or his/her NMDP
designee and the Protocol Officer or his/her NMDP designee will notify stakeholders as appropriate in the event a CCR5delta32 homozygous donor is identified (as well as all CCR5 homozygous donors as described above). Confirmatory CCR5 testing will be performed in CLIA-certified lab at the time of donor work-up.  
4) The Protocol Officer and/or his/her NMDP designee will assist the NMDP teams with the process.
appendix i nmdp procedure for
references

Hütter G, Nowak D, Mossner M, Ganepola S, Mußig A, Allers K, Schneider T, Hofmann J,
Kücherer K, Blau O, Blau IW, Hofmann WK, Thiel E. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation. *New Engl J Med.* 2009; 360:692-8. Galvani A, Novembre J. The evolutionary history of the CCR5-D32 HIV-resistance mutation. Microbes *Infect*. 2005; 7: 302–309.
appendix i nmdp procedure for
ccr5delta32 testing laboratory information

CLIA-Certified Laboratory Susan H. Hsu, PhD Director, Histocompatibility / Molecular Genetics American Red Cross Blood Services Penn-Jersey Region 700 Spring Garden St Histocompatibility/Molecular Genetics Dept Philadelphia, PA 19123-3594 Phone : (215) 451-4273 Fax : (215) 451-2535 E-mail : shsu@usa.redcross.org
appendix i nmdp procedure for
appendix j references

Balsalobre, P., J. L. Diez-Martin, et al. (2009). "Autologous stem-cell transplantation in patients with HIV-related lymphoma." J Clin Oncol 27(13): 2192-8. Contu, L., G. La Nasa, et al. (1993). "Allogeneic bone marrow transplantation combined with multiple anti-HIV-1 treatment in a case of AIDS." Bone Marrow Transplant 12(6): 669-71. Gabarre, J., V. Leblond, et al. (1996). "Autologous bone marrow transplantation in relapsed HIV-related non-Hodgkin's lymphoma." Bone Marrow Transplant 18(6): 1195-7.  
Giri, N., M. R. Vowels, et al. (1992). "Failure of allogeneic bone marrow transplantation to benefit HIV infection." J Paediatr Child Health 28(4): 331-3. Gupta, V., M. Tomblyn, et al. (2009). "Allogeneic hematopoietic cell transplantation in human immunodeficiency virus-positive patients with hematologic disorders: a report from the center for international blood and marrow transplant research." Biol Blood Marrow Transplant 15(7): 864-71. Hamadani, M. and S. M. Devine (2009). "Reduced-intensity conditioning allogeneic stem cell transplantation in HIV patients with hematologic malignancies: yes, we can." Blood 114(12): 2564-6. Holland, H. K., R. Saral, et al. (1989). "Allogeneic bone marrow transplantation, zidovudine, and human immunodeficiency virus type 1 (HIV-1) infection. Studies in a patient with non-Hodgkin lymphoma." Ann Intern Med 111(12): 973-81.  
Hutter, G., D. Nowak, et al. (2009). "Long-term control of HIV by CCR5 Delta32/Delta32 stemcell transplantation." N Engl J Med 360(7): 692-8.  
Kang, E. M., M. de Witte, et al. (2002). "Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome." Blood 99(2): 698-701. Krishnan, A., A. Molina, et al. (2005). "Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas." Blood 105(2): 874-8. Re, A., C. Cattaneo, et al. (2003). "High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy." J Clin Oncol 21(23): 4423-7. Rossi, G., A. Donisi, et al. (1999). "The International Prognostic Index can be used as a guide to treatment decisions regarding patients with human immunodeficiency virus-related systemic non-Hodgkin lymphoma." Cancer 86(11): 2391-7. Seaberg, E. C., D. Wiley, et al. "Cancer incidence in the multicenter aids cohort study before and during the HAART era: 1984 to 2007." Cancer. Serrano, D., R. Carrion, et al. (2005). "HIV-associated lymphoma successfully treated with peripheral blood stem cell transplantation." Exp Hematol 33(4): 487-94. Sora, F., A. Antinori, et al. (2002). "Highly active antiretroviral therapy and allogeneic CD34(+) peripheral blood progenitor cells transplantation in an HIV/HCV coinfected patient with acute myeloid leukemia." Exp Hematol 30(3): 279-84.  
Spitzer, T. R., R. F. Ambinder, et al. (2008). "Dose-reduced busulfan, cyclophosphamide, and autologous stem cell transplantation for human immunodeficiency virus-associated lymphoma: AIDS Malignancy Consortium study 020." Biol Blood Marrow Transplant 14(1): 59-66. Torlontano, G., P. Di Bartolomeo, et al. (1992). "AIDS-related complex treated by antiviral drugs and allogeneic bone marrow transplantation following conditioning protocol with busulphan, cyclophosphamide and cyclosporin." Haematologica 77(3): 287-90. Vilmer, E., A. Rhodes-Feuillette, et al. (1987). "Clinical and immunological restoration in patients with AIDS after marrow transplantation, using lymphocyte transfusions from the marrow donor." Transplantation 44(1): 25-9. Wolf, T., V. Rickerts, et al. (2007). "First case of successful allogeneic stem cell transplantation in an HIV-patient who acquired severe aplastic anemia." Haematologica 92(4): e56-8. Woolfrey, A. E., U. Malhotra, et al. (2008). "Generation of HIV-1-specific CD8+ cell responses following allogeneic hematopoietic cell transplantation." Blood 112(8): 3484-7.