Evaluation of the Use of Antiretroviral Regimens Containing Raltegravir for Prophylaxis of Mother-to-child-transmission of HIV Infection in Pregnant Women Presenting With Detectable Viral Load After 32 Weeks of Gestation: a Pilot Study
Phase: PHASE2
Conditions: HIV, Pregnancy
Sponsor: Fundação Bahiana de Infectologia

Version 2 – 08/03/2011 
1 
 
Title: 
Evaluation of the use of antiretroviral regimens containing 
Raltegravir for prophylaxis of mother-to-child-transmission of HIV 
infection in pregnant women presenting with detectable viral load 
after 28 weeks of gestation: a pilot study 
 
 
CARLOS BRITES, MD, PhD  
UNIVERSIDADE FEDERAL DA BAHIA TEL. 557192329552 
EMAIL: crbrites@gmail.com 
 
Date: Aug 3, 2011 
 
NCT01854762 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Version 2 – 08/03/2011 
2 
 
   
1. Background and rationale: 
 The current available antiretroviral (ARV) agents make possible a successful treatment 
of virtually all HIV-infected patients, even those heavily experienced subjects, with a 
history of previous failure to ARV drugs of different classes (1-3). The introduction of 
new drug classes was determinant to this achievement, since most of viral strains are 
susceptible for such drugs, allowing treating experienced patients as if they were drug 
naïve (3). However, some problems are still present, especially for specific populations, 
like pregnant women and infants. For these groups, most of currently available drugs are 
not 
used, 
because 
the 
lack 
of 
information 
on 
safety, 
efficacy, 
and 
pharmacokinetic/dynamic behavior of ARVs drugs (4-8).    
The MTCT is still a problem in certain areas of the world, especially in resource limited 
settings. It has been demonstrated that the introduction of active ARV therapy for 
pregnant women, leading to suppression of HIV viremia by the end of pregnancy is a 
crucial step in the interruption of MTCT (9-11). Pregnant women that reaches a viral 
load below 1,000 copies of HIV-1 RNA/ml of plasma, by the end of pregnancy, has a  
decrease in the rates of HIV-1 transmission to less than 2% (10,11). However, some 
women presents with multi-drug resistant HIV-1 strains, making difficult the choice of 
an active ARV regimen, since some drugs are not recommended in pregnancy (12,13). 
On the other hand, in some settings, women often present to their first antenatal care 
visit late in the pregnancy, posing an additional problem: how to effectively treat these 
patients to assure they will have an undetectable viral load at the moment of delivering? 
Depending on the plasma viremia magnitude, and viral susceptibility it can take 6 or 
more weeks to reduce the viral load to less than the desired 1,000 copies of HIV-1 RNA 
/ ml of plasma.  To achieve this goal, it would be necessary the use of a potent, very 
efficacious ARV regimen that could provide such viral decay in a very short period of 
time.  
In Salvador, Brazil, most of HIV-infected pregnant women are attended in the CEDAP, 
a referral center for AIDS care. In average, 120 pregnant women are attended at the 
center every year.  An estimated 40% are late-presenters, and have their first medical 
evaluation with a gestational age higher than 30 weeks. The remaining 60% are already 
on follow up in the center, or arrive early in the course of pregnancy. However, about 
15% of them has some degree of resistance to ARV drugs, and start antenatal care with 
detectable viral load. Other important point, around 8% of these women are coinfected 

Version 2 – 08/03/2011 
3 
 
by another human retrovirus, the HumanT-cell  Lymphotropic Virus type 1 (HTLV-1), 
which has a life cycle similar to that found in HIV-1, and shares a great similarity 
between replication enzymes, like reverse transcriptase (RT) and integrase, with HIV-1 
(14,16). In vitro studies have demonstrated that most nucleoside   reverse transcriptase 
inhibitors active against HIV-1 are also effective in blocking the HTLV-1 RT activity. 
Preliminary studies conducted by our group have shown that coinfection with these two 
agents was associated with a much higher rate of transmission of both viruses (12). The 
MTCT of at least one of these agents was detected in 63% of 96 coinfected women. 
Even considering the fact that they probably did not receive any MTCT prophylaxis, the 
transmission rate was much higher than one could expect. It suggests that coinfection 
may enhance MTCT for both, HIV-1 and HTLV-1.    
Raltegravir (RAL), the first HIV-1 integrase inhibitor, is a potent and safe ARV drug 
(18). The available evidence suggests that it has no genotoxic potential, and promotes a 
rapid decline in HIV-1 plasma viremia. In addition, RAL is highly active against viral 
strains presenting different  degrees of resistance to other ARV drugs. Thus, RAL could 
be an ideal candidate to be used for prevention of MTCT for women with detectable 
viral load, presenting late in the course of pregnancy. Another attractive point is to 
consider that, due to the similarity between the integrase enzyme of HIV-1 and HTLV1, 
RAL could be active against HTLV-1, blocking its replication. If our hypothesis is 
correct, the use of RAL-containing ARV regimens would reduce the MTCT of both 
agents.  
2. Objectives 
 Primary:   
=>to evaluate the efficacy of RAL containing ARV regimens, compared to a SOC 
therapy in providing a HIV-1 RNA plasma viral load below 50 copies/ml, at the end of 
pregnancy, for late-presenters HIV-1-infected women.   
Secondary:   
=>to evaluate the time to viral suppression in pregnant women using RAL based 
regimens and comparators;  
=>to compare the frequency of adverse events for women using RAL-based ARV 
regimens and comparators, and for their babies;  
=> to evaluate the frequency of MTCT  of HIV-1 and HTLV-1 for pregnant women 
using RAL-based regimens or comparators;  
  

Version 2 – 08/03/2011 
4 
 
2.1.1 Clinical hypotheses.   
  
- 
RAL-based ARV regimens are able to suppress HIV viremia in late-presenters 
pregnant women to undetectable levels at the moment of delivery;  
- 
RAL-based regimens are safe for use in pregnant women, and able to prevent  
MTCT  
- 
RAL-based regimens are able to prevent MTCT of both, HIV and HTLV, in 
pregnant, coinfected women  
3. Study design:  This is an exploratory, pilot study to compare the safety and efficacy of 
RAL-containing ARV regimens and standard of care (SOC - AZT+3TC+LPV/r) therapy 
for the prophylaxis of HIV-1 and HTLV-1 MTCT, in Bahia, Brazil. Sample size:  We 
intend to enroll pregnant women who accept to participate in the study. We estimate a 
total of 180 pregnant women will be attended in a 18 months period. From this group, 
we expect that at least 50 patients will be “late-presenters”, and eligible to enter the 
study. Considering a 8% prevalence of coinfection by HTLV-1, we expect to detect 4-5 
coinfected women.  
Study procedures- Forty drug-naïve women initiating ARV therapy during “late” 
(gestational age equal or higher than 28 weeks) pregnancy will be invited to enter the 
study. They will be randomly assigned to receive a RAL-based ARV regimen 
(AZT+3TC+RAL), or SOC therapy (AZT+3TC+LPV/r). All HTLV-positive women 
will be assigned to the RAL arm. Baseline plasma samples will be stored to genotyping 
for all patients, but the women will be tested only if they present detectable viral load at 
the end of the trial, for detection of primary resistance mutations. We intend to include 
22 patients in each arm of the study. Participation in the study will be offered to all 
eligible women attending routine medical visits, and they will be included consecutively 
until we reached the intended number (22 in each arm). Rates of MTCT for both agents 
will be assessed by molecular detection of HIV-1 and/or HTLV-1 in plasma (HIV-1) 
and PBMC (both agents) of newborns, after 4 weeks of delivery. After delivering, all 
women will be referred to their assistant physicians, in order to define if they will 
continue on ARV therapy or if they interrupt it. The patients enrolled in RAL will 
switch to SOC treatment if they are recommended to maintain ARV treatment, since the 
Brazilian Ministry of Health guideline does not recommend RAL as part of initial ARV 
regimens.  

Version 2 – 08/03/2011 
5 
 
The main study endpoint will be the proportion of patients in each arm with HIV-1 RNA 
viral load < 50 copies/ml at the end of pregnancy.  
 Secondary endpoints:  
- 
the time for achieving a VL below 50 copies/ml,  
- 
the rate of MTCT for  HIV-1 and / or HTLV-1  
- 
Frequency of adverse events for women receiving RAL or SOC therapy  
- 
Frequency of adverse events for babies born from all mothers included in the 
study, until completing 6 months of age   
Inclusion criteria:  
- 
Pregnant women with confirmed HIV-1 infection (positive Western blot or 
plasma HIV-1 RNA >1,000 copies/ml)  
- 
Gestational age higher than 28 weeks  
- 
Age equal or higher than 18 years  
- 
HIV-1 plasma viral load ≥ 1,000 copies of HIV-1 RNA/ml  
- 
HTLV serology result  
- 
ARV naïve  
- 
Any CD4 count  
Exclusion criteria  
- 
Previous use of any ARV  
- 
Age lower than 18 years  
- 
Undetectable plasma viral load at screening  
  
  
Study Flowchart  
                                                                          
 -44 pregnant women who meet  inclusion criteria:  
 
  
- Age equal or higher than 18 years  
 
  
-HIV-1 PVL ≥ 1,000 copies of HIV- 
  

Version 2 – 08/03/2011 
6 
 
 
  
 
AZT+3TC+RAL  
(N=22)  
AZT+3TC+LPV-r 
(N=22)  
  
  
  
  
delivery          4 weeks      24 weeks  
 
 6 weeks (mothers) +  4 and 24 weeks (newborns)  
  
  
  
  
  
2.5.1. Study timetable  
Procedure  
Baseline  Week  
2  
Week  
4  
Week  
5  
Week  
6  
Week  
4  
(newborn)  
Week  24  
(newborn)  
Informed 
consent   
      X  
  
  
  
  
  
  
Inclusion / 
Exclusion 
criteria  
X  
  
  
  
  
  
  
Medical   
History  
X  
X  
X  
X  
X  
X  
X  
Adverse 
events  
  
X  
X  
X  
X  
  
X  
HIV-1 Viral  
Load  
X  
X  
X  
X  
X  
X  
  
CD4/8 count  
X  
  
X  
  
X  
  
  
  
  

Version 2 – 08/03/2011 
7 
 
Chemistry  
  
X  
X  
X  
X  
X  
X  
X  
Hematology  
X  
X  
X  
X  
X  
X  
  
X  
  
Plasma 
sample  
(storage)  
X  
  
  
  
  
  
  
HIV /  
HTLV  
Proviral 
load   
  
  
  
  
  
X  
  
HTLV  
serology  
X  
  
  
  
  
  
  
 
  
 
 
2.5.2. Critical evaluations at baseline  
Written informed consent (IC) must be obtained from each women before any study initial evaluation 
procedure be performed. The informed consent must be previously approved by institutional IRB. After 
signing the IC the women will conclude the initial evaluation to define their eligibility to enter the 
protocol. Following recruitment, patients will be randomly l assigned to one of the study arms, and will 
receive a sequential protocol number. Each patient will receive only one allocation number.  
  
2.5.3. Period of initial evaluation  
Patients will be randomized as soon as they conclude the initial evaluation. All results of initial 
evaluation must be available before randomization.  
Patients fulfilling the eligibility criteria will be randomized, and will receive a randomization number. 
The will not be eligible for a new initial evaluation if they were excluded from the study after 
randomization was completed, for any reason.  
  
2.5.4. Efficacy evaluation  
Plasma samples will be collected in each time point, according to the table above, for HIV-1 RNA viral 
load measurement. The method for VL measurement will be b-DNA or Real-Time PCR, with a limit of 
detection established in 50 copies/ml, or lower. CD4/8+ cells count will be determined by flow 

Version 2 – 08/03/2011 
8 
 
cytometry.  
The primary efficacy parameter will be the HIV-1 RNA VL<50 copies/ml at week 6 (end of pregnancy), 
using an algorithm missing, switch, discontinuation = Failure (MSDF), according to FDA snapshot 
algorithm.  
Secondary parameters of efficacy will include the following:  
- 
the time for achieving a VL below 50 copies/ml, and  
- 
the rate of MTCT for  HIV-1 and / or HTLV-1  
2.5.5. Safety evaluations will consist of monitoring and report of all adverse events and serious adverse 
events for women receiving RAL or SOC therapy, and for their babies, until completing 6 months of 
age. Safety will be assessed through regular physical examination, and laboratory monitoring of 
hematology, lipids, glucose, liver enzymes, and creatinine levels. All detected abnormalities in lab 
results will be reported in CRF.  
The laboratory parameters to be tested will be:  
-White blood cells count, hemoglobin, platelets  
-Fasting glucose, Total Cholesterol, LDL, HDL, and VLDL cholesterol, triglycerides.  
- 
Creatinine, ALT, AST, Alcaline Phosphatase.  
  
2.5.6. Safety parameters  
-Incidence and severity of AEs and laboratory abnormalities  
- 
absolute values and changes in results overtime  
Proportion of patients interrupting therapy due to AEs 
- Changes in baseline physical examination  
  
2.5.7. Toxicity control  
The occurrence of AE during the study period will be evaluated by the investigator, and classified 
according to the toxicity scales of AIDS Division (DAIDS).  
The safety of Raltegravir in pregnant women was not completely defined, and the investigational product 
will can be interrupted by the investigator, according to the severity of AE. No reduction on RAL doses 
will be allowed. All change in the use of RAL must be reported in CRF. In the case of the need of 
interruption of RAL, the drug will be switched to LPV/r.  
Patients presenting a grade 1 or 2 AE will continue to receive RAL, at Investigator discretion. Patients 
presenting a grade 3 AE can keep using RAL, if the investigator consider the toxicity was not caused by 

Version 2 – 08/03/2011 
9 
 
the drug, but if the AE is considered to be caused by RAL, or if it is classified as grade 4, the drug must 
be interrupted.  
  
2.5.8. Patients follow up  
All patients included in the protocol will be evaluated at baseline, and after 2, 3, 4, 5 and 6 weeks. The 
newborns will be assessed by a blood collection after 4 weeks, and to a clinical and laboratory evaluation 
after 24 weeks, to assess any potential AE caused by their mother´s treatment.  
  
  
Study duration: We intend to recruit the total sample in a 12 months period. Additional 
6 months will be spent on newborns evaluation, statistical analysis, and final reviews / 
reports. Thus, the intended duration of the study will be 18 months.  
 Sample size justification   
  
This will be an exploratory, pilot study. Power considerations will not apply.   
  
 
 
2.7.2 Plan for Statistical Summaries and Analyses  
General Considerations  
All statistical summaries and analysis will be provided for the intent-to-treat population, 
defined as all patients who are randomized to treatment.  Summaries and analyses of the 
baseline data and efficacy data will also be provided for the efficacy-evaluable 
population, defined as patients who meet the inclusion/exclusion criteria, take at least 
80% doses of study medication, and complete the Week 6 (or termination) visit.    
With the exception of the analysis of the primary efficacy endpoint, percentage of 
responders for the intent-to-treat population, missing data will not be estimated or 
carried forward in any statistical analyses.    

Version 2 – 08/03/2011 
10 
 
All comparisons of the treatment groups will be performed using two-sided tests at a 
0.05 level of significance (  = 0.05).  The null hypothesis for all analyses is that there is 
no difference between the treatment groups.  
All summaries, statistical analyses, and individual patient data listings described below 
will be provided in separate appendices.  Separate listings will be provided for each of 
the treatment groups in the intent-to-treat population as well as for the group of patients 
not randomized.  
Disposition of Patients  
Summaries of the number of patients randomized, the number of those completing the 
study, and the incidence of protocol violations will be provided for each treatment 
group.  
The number (%) of patients with protocol violations that might affect endpoints of the 
study will be based on review of the database.  This assessment will be made prior to 
determination of treatment assignment for all patients in the database.  
Demographic and Disease Characteristics  
The statistical analyses described below will be completed for:  
the intent-to-treat patient population the 
efficacy-evaluable population  
Demographic Characteristics  
The following table identifies the demographic and disease characteristics used to 
determine the comparability of the treatment groups and the methods used to analyze 
them.    
                        
  
Table 1: Variables Assessed to Determine Comparability  
Variable  
Method of Analysis  
Gestational Age at randomization  
One-way  
ANOVA/KW  
Gestational Age at randomization  
One-way  
ANOVA/KW  

Version 2 – 08/03/2011 
11 
 
Baseline VL  
One-way  
ANOVA/KW  
Baseline CD4  
One-way  
ANOVA/KW  
  
Efficacy Endpoints  
The statistical analyses described below will be completed for:  
the intent-to-treat patient population the 
efficacy-evaluable population  
The primary efficacy endpoint is the number (%) of patients achieving the primary 
endopoint (HIV-1 RNA Viral Load <50 copies/ml) at the Week 6 (or termination) visit.    
Patients will be counted as non-responders if they are missing Week 6 (or termination).  
The Raltegravir treatment group will be compared to SOC group with respect to 
percentage of responders using a Chi-square test.  Two-sided 95% confidence intervals 
for the percentage of responders will be calculated for each treatment group.   
The following table identifies the secondary efficacy endpoints and the methods used to 
analyze them.  
Table 2 - Variables Assessed to Evaluate the main endpoints  
Frequency of Adverse events  (mother and 
newborns)  
Chi-square test  
Time to reach VL below 50 copies  
One-way  
ANOVA/KW  
% MTCT (HIV, HTLV)  
Chi-square test  
  
For each of these variables, the Raltegravir treatment group will be compared to the 
SOC group.    
Safety Endpoints  
The summaries and statistical analyses of the safety endpoints will be completed for the 
intent-to-treat population.  The incidence of at least one Grade III or IV adverse event 
will be the primary safety endpoint of the study.  The treatment groups will be compared 

Version 2 – 08/03/2011 
12 
 
with respect to the percentage of patients with at least one Grade III or IV adverse event 
using a Chi-square test.    
Summaries of the number (%) of subjects in each treatment group with at least one 
adverse event, classified according to preferred term and body system, will also be 
provided for:  
- 
drug-related adverse events  
- 
serious adverse events  
Secondary safety endpoints are the incidence of adverse events classified according to 
preferred term and body system, clinically significant laboratory test results, and 
changes in vital signs.  The treatment groups will be compared with respect to the 
percentage of patients with clinically significant laboratory test results at the Week 2, 4, 
5, or 6 Visits using Chi-square tests.  Summaries of the physical examination data, vital 
signs (actual value and change from baseline), and laboratory data (actual value and 
change from baseline) at each visit will be provided.   
Power/Sample Size:  
  
Since this is a pilot study, power considerations does not apply.  
  
Specific Drug Supply Requirements The RAL open label supply will be provided by  
Merck. The additional study drugs (AZT+3TC, LPV/r) will be provided by the  
Brazilian AIDS Program, since they are part of SOC procedures The 
drugs must be supplied as its commercial presentation.    
Adverse Experience Reporting - The investigator and the site team will be responsible 
for detection, documentation, and reporting of any events that fulfill the AE definition. 
AE is defined as any undesired medical event occurring in a patient or individual 
involved in a clinical investigation protocol, which may be transiently associated to the 
use a medical product, independently of being considered related or not to the 
investigational product. A serious adverse event (SAE) is defined as any medical 
occurrence that results in death, or that be life-threatening, needs or makes 
hospitalization longer, results in deficiency/disability, be a congenital anomaly/birth 
defect, all liver injuries grade 3 or higher, caused by drugs  

Version 2 – 08/03/2011 
13 
 
References  
1 
– Willig JH, Abroms S, Westfall AO, et al. Increased regimen durability in the 
era of once-daily fixed-dose combination antiretroviral therapy. AIDS. 
2008;22(15):19511960.  
2 
- 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.  
January  
10,  
2011;  1–166. 
 
Available  
at 
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.  
2 - Nozza S, Galli L, Visco F, et al. Raltegravir, maraviroc, etravirine: an effective 
protease inhibitor and nucleoside reverse transcriptase inhibitor-sparing regimen for 
salvage therapy in HIV-infected patients with triple-class experience. AIDS 2010; 
24 (6): 924-8.  
3 McKeown DA, Rosenvinge M, Donaghy S, Sharland M, Holt DW, Cormack I, Hay  
P,  
Sadiq ST. High neonatal concentrations of raltegravir following transplacental 
transfer in HIV-1 positive pregnant women. AIDS. 2010 Sep 24;24(15):2416-8.  
4 – Johnson M. Raltegravir use in special populations. Eur J Med Res. 2009 Nov 
24;14 Suppl 3:43-6.   
5 – Placeres Alsina MM, Tuset Creus M, Miró JM. [Pharmacokinetics and interactions 
of raltegravir]. Enferm Infecc Microbiol Clin. 2008 Nov;26 Suppl 12:23-8  
6 Jaworsky D, Thompson C, Yudin MH, Bitnun A, Brophy J, Samson L, Antoniou T, 
Loutfy MR. Use of newer antiretroviral agents, darunavir and etravirine with or 
without raltegravir, in pregnancy: a report of two cases.  
7 Taylor N, Touzeau V, Geit M, Gisinger M, Egle A, Greil R, Rieger A, ZangerleR. 
Raltegravir in pregnancy: a case series presentation. Int J STD AIDS. 2011 
Jun;22(6):358-60.  
8 Johri M, Ako-Arrey D. The cost-effectiveness of preventing mother-to-child 
transmission of HIV in low- and middle-income countries: systematic review. Cost 
Eff Resour Alloc. 2011 Feb 9;9:3.   
9 – Mahy M, Stover J, Kiragu K, Hayashi C, Akwara P, Luo C, Stanecki K, Ekpini R, 
Shaffer N. What will it take to achieve virtual elimination of mother-to-child 

Version 2 – 08/03/2011 
14 
 
transmission of HIV? An assessment of current progress and future needs. Sex 
Transm Infect. 2010 Dec;86 Suppl 2:ii48-55.  
10 Mepham SO, Bland RM, Newell ML. Prevention of mother-to-child transmission of 
HIV in resource-rich and -poor settings. BJOG. 2011 Jan;118(2):202-18.  
11 Huntington SE, Bansi LK, Thorne C, Anderson J, Newell ML, Taylor GP, Pillay D,  
Hill T, Tookey PA, Sabin CA; on behalf of the UK Collaborative HIV Cohort (UK  
CHIC) Study and the National Study of HIV in Pregnancy and Childhood (NSHPC). 
Treatment switches during pregnancy among HIV-positive women on antiretroviral 
therapy at conception. AIDS. 2011 Jun 13.  
12 Weinberg A, Forster-Harwood J, Davies J, McFarland EJ, Pappas J, Kinzie K, Barr 
E, Paul S, Salbenblatt C, Soda E, Vazquez A, Levin MJ. Safety and tolerability of 
antiretrovirals during pregnancy. Infect Dis Obstet Gynecol.  
2011;2011:867674  
13 - Derse D, Crise B, Li Y, Princler G, Lum N, Stewart C, McGrath CF, Hughes SH, 
Munroe DJ, Wu X. Human T-cell leukemia virus type 1 integration target sites in 
the human genome: comparison with those of other retroviruses. J Virol. 2007 
Jun;81(12):6731-41.  
14 Rabaaoui S, Zouhiri F, Lançon A, Leh H, d'Angelo J, Wattel E. Inhibitors of strand 
transfer that prevent integration and inhibit human T-cell leukemia virus type 1 early 
replication. Antimicrob Agents Chemother. 2008 Oct;52(10):3532-41.  
15 - Seegulam ME, Ratner L. Integrase inhibitors effective against human T-cell 
leukemia virus type 1. Antimicrob Agents Chemother. 2011 May;55(5):2011-7.   
16 – Celia pedroso, Neide Weyll, Carlos Brites. HIV-HTLV-1 coinfection is associated 
with higher rates of mother-to-child-transmission, and a shorter survival time in 
children in Bahia, Brazil. XVIII Intl. AIDS Conference, July 18-23, 2010 Vienna, 
Abst. THPEO214.  
17 Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background 
therapy for resistant HIV-1 infection. N Engl J Med. 2008;359(4):339354.