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Acyclovir to Treat Patients Co-infected With HIV and Herpes Viruses in Uganda

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ClinicalTrials.gov Identifier: NCT00405821
Recruitment Status : Completed
First Posted : November 30, 2006
Results First Posted : September 28, 2012
Last Update Posted : September 28, 2012
Sponsor:
Collaborators:
University of Washington
Johns Hopkins University
Translational Genomics Research Institute
Information provided by (Responsible Party):
Steven Reynolds, National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions HIV Infections
Herpes Genitalis
Interventions Drug: Acyclovir
Drug: Placebo
Enrollment 440
Recruitment Details 440 HIV+ subjects recruited in rural Rakai, Uganda within the Rakai Health Sciences Program mobile medical clinic during May 2007 thru November 2008
Pre-assignment Details All subjects were randomized to study arm, and initiated study treatment at the time of enrollment.
Arm/Group Title Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Hide Arm/Group Description [Not Specified] [Not Specified]
Period Title: Overall Study
Started 220 220
Completed 198 198
Not Completed 22 22
Reason Not Completed
Death             5             7
Lost to Follow-up             7             7
Protocol Violation             1             0
initiated ART             9             8
Arm/Group Title Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily Total
Hide Arm/Group Description [Not Specified] [Not Specified] Total of all reporting groups
Overall Number of Baseline Participants 220 220 440
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 220 participants 220 participants 440 participants
20-29 years 46 44 90
30-39 years 94 93 187
40-49 years 54 53 107
50+ years 26 30 56
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 220 participants 220 participants 440 participants
Female
150
  68.2%
161
  73.2%
311
  70.7%
Male
70
  31.8%
59
  26.8%
129
  29.3%
1.Primary Outcome
Title Progression to AIDS (CD4+ Less Than 250 Cells/Microliter or World Health Org Stage IV dx, Excluding Esophageal Candidiasis)
Hide Description Evaluate the effect of acyclovir prophylaxis vs placebo among HIV-1/HSV-2 co-infected individuals on the progression to AIDS (CD4+ less than 250 cells/microliter or World Health Org stage IV disease, excluding esophageal candidiasis)
Time Frame 2 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat analysis of all subjects randomized on the trial meeting the primary endpoint
Arm/Group Title Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 220 220
Measure Type: Number
Unit of Measure: participants
95 110
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Acyclovir 400mg Tablet Twice Daily, Placebo Tablet Twice Daily
Comments Intent-to-treat analysis used Cox proportional hazards (CPH) models, adjusting for baseline log10 viral load (VL), CD4 cell count, gender and age to assess the risk of disease progression
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments P-value was adjusted to include multiple looks at data including an interim efficacy review at 50% and 75% accrual of person-years on study
Method Regression, Cox
Comments adjusted for baseline log10 viral load, baseline CD4 count, gender, and age
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.58 to 0.99
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Difference in Number of Episodes of Genital Ulcer Disease Between Arms
Hide Description We calculated incidence rate for each treatment arm for episodes of genital ulcer disease, and incidence rate ratio.
Time Frame 2 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
We conducted monthly clinical assessment for GUD on all randomized subjects during their entire follow-up period on this trial. The number of episodes of GUD is shown below.
Arm/Group Title Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 220 220
Measure Type: Number
Unit of Measure: episodes
27 47
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Acyclovir 400mg Tablet Twice Daily, Placebo Tablet Twice Daily
Comments Null hypothesis is no difference by treatment arm in rate of GUD.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments we included multiple GUD events per subject in the estimate of GUD incidence
Method rate ratio with 95% CI
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.31
Confidence Interval (2-Sided) 95%
0.19 to 0.48
Estimation Comments [Not Specified]
3.Secondary Outcome
Title HIV-1 Viral Load Difference Between Arms
Hide Description We measured mean annual rate of change in log10 viral load (copies/mL) for each group. We assessed difference in annual rate of change in log10 viral load (copies/mL) between groups.
Time Frame baseline, 6 months, 12 months, 18 months, 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
We measured viral load at baseline and at 6 monthly follow-up visits during 24 months of follow-up for all subjects randomized on this study.
Arm/Group Title Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 220 220
Mean (95% Confidence Interval)
Unit of Measure: log10 (copies/mL)
-0.061
(-0.250 to 0.129)
0.402
(0.212 to 0.592)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Acyclovir 400mg Tablet Twice Daily, Placebo Tablet Twice Daily
Comments Null hypothesis is no difference in annual rate of change in log10 viral load by arm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.463
Confidence Interval (2-Sided) 95%
-0.731 to -0.194
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Toxicity of Acyclovir
Hide Description [Not Specified]
Time Frame 2 years
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Adherence to Acyclovir
Hide Description [Not Specified]
Time Frame 2 years
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Virologic and Immunologic Responses to ART in Those Who Progress to CD+4 Less Than 250cells/mL
Hide Description [Not Specified]
Time Frame 6 months and 12 moths post ART initiation
Outcome Measure Data Not Reported
Time Frame maximum follow-up time on this study ranged from 24 months to 41 months depending on time of enrollment.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   75/220 (34.09%)      85/220 (38.64%)    
Blood and lymphatic system disorders     
Anemia   7/220 (3.18%)  9 13/220 (5.91%)  16
Gastrointestinal disorders     
Peptic ulcer disease   1/220 (0.45%)  1 0/220 (0.00%)  0
Cholecystitis   1/220 (0.45%)  1 0/220 (0.00%)  0
Hepatotoxicity   0/220 (0.00%)  0 1/220 (0.45%)  1
Abdominal pain, unspecified   1/220 (0.45%)  1 3/220 (1.36%)  3
General disorders     
Dehydration   1/220 (0.45%)  1 0/220 (0.00%)  0
Febrile Illness, unspecified   5/220 (2.27%)  5 5/220 (2.27%)  6
Infections and infestations     
TB Adenitis   1/220 (0.45%)  1 1/220 (0.45%)  1
Malaria   26/220 (11.82%)  29 24/220 (10.91%)  34
Mastitis   1/220 (0.45%)  1 0/220 (0.00%)  0
skin infection, unspecified   1/220 (0.45%)  1 1/220 (0.45%)  1
EENT infection, unspecified   1/220 (0.45%)  1 1/220 (0.45%)  1
Bacterial pneumonia   3/220 (1.36%)  3 2/220 (0.91%)  2
Pulmonary Tuberculosis   13/220 (5.91%)  13 13/220 (5.91%)  14
Extra-pulmonary tuberculosis   2/220 (0.91%)  2 0/220 (0.00%)  0
Upper respiratory tract infection   1/220 (0.45%)  1 1/220 (0.45%)  1
Lower respiratory tract infection   1/220 (0.45%)  1 0/220 (0.00%)  0
Cryptococcal meningitis   0/220 (0.00%)  0 1/220 (0.45%)  1
Esophageal candidiasis   0/220 (0.00%)  0 1/220 (0.45%)  1
Gastroenteritis   0/220 (0.00%)  0 2/220 (0.91%)  2
Genito-urinary disease (GUD)   1/220 (0.45%)  1 0/220 (0.00%)  0
Cystitis   1/220 (0.45%)  1 0/220 (0.00%)  0
Urinary Tract Infection   2/220 (0.91%)  2 0/220 (0.00%)  0
Injury, poisoning and procedural complications     
Trauma to chest   2/220 (0.91%)  2 0/220 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Kaposi's sarcoma   1/220 (0.45%)  1 2/220 (0.91%)  2
Pregnancy, puerperium and perinatal conditions     
Abortion   2/220 (0.91%)  2 1/220 (0.45%)  1
Pregnancy   30/220 (13.64%)  37 41/220 (18.64%)  52
Pregnancy complication, unspecified   5/220 (2.27%)  5 2/220 (0.91%)  2
Reproductive system and breast disorders     
Pelvic inflammatory disease   1/220 (0.45%)  1 1/220 (0.45%)  1
Respiratory, thoracic and mediastinal disorders     
Respiratory complaint, unspecified   1/220 (0.45%)  1 0/220 (0.00%)  0
Pleural effusion   1/220 (0.45%)  2 0/220 (0.00%)  0
Skin and subcutaneous tissue disorders     
wound, unspecified   1/220 (0.45%)  1 2/220 (0.91%)  2
Vascular disorders     
Hypertension   0/220 (0.00%)  0 1/220 (0.45%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Acyclovir 400mg Tablet Twice Daily Placebo Tablet Twice Daily
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   219/220 (99.55%)      218/220 (99.09%)    
Cardiac disorders     
Palpitations   32/220 (14.55%)  41 41/220 (18.64%)  58
Ear and labyrinth disorders     
Hearing Loss   14/220 (6.36%)  16 15/220 (6.82%)  16
Eye disorders     
Allergic conjunctivitis   33/220 (15.00%)  41 21/220 (9.55%)  29
Gastrointestinal disorders     
Peptic ulcer disease   63/220 (28.64%)  124 60/220 (27.27%)  115
Gastritis   27/220 (12.27%)  31 33/220 (15.00%)  42
Gastrointestinal, other complaint   168/220 (76.36%)  415 157/220 (71.36%)  488
General disorders     
Lymphadenopathy   25/220 (11.36%)  30 36/220 (16.36%)  47
Decreased appetite   30/220 (13.64%)  35 29/220 (13.18%)  33
General complaint, unspecified   190/220 (86.36%)  791 187/220 (85.00%)  810
General complaint, unspecified   115/220 (52.27%)  217 123/220 (55.91%)  252
Infections and infestations     
Malaria   107/220 (48.64%)  211 105/220 (47.73%)  204
fungal skin infection   64/220 (29.09%)  102 46/220 (20.91%)  70
angular chelitis   21/220 (9.55%)  23 34/220 (15.45%)  45
Rhinitis   20/220 (9.09%)  20 18/220 (8.18%)  20
Conjunctivitis   29/220 (13.18%)  34 32/220 (14.55%)  40
Upper respiratory tract infection   212/220 (96.36%)  1242 212/220 (96.36%)  1226
Oral candidiasis   15/220 (6.82%)  26 23/220 (10.45%)  40
Intestinal helminthiasis   12/220 (5.45%)  12 20/220 (9.09%)  25
Gastroenteritis   41/220 (18.64%)  55 33/220 (15.00%)  55
Gonorrhea   14/220 (6.36%)  20 12/220 (5.45%)  14
Genito-urinary disease (GUD)   39/220 (17.73%)  52 77/220 (35.00%)  131
Vaginal candidiasis   80/220 (36.36%)  134 79/220 (35.91%)  159
Urinary Tract Infection   36/220 (16.36%)  48 39/220 (17.73%)  55
Injury, poisoning and procedural complications     
Traumatic injury   16/220 (7.27%)  18 16/220 (7.27%)  16
Musculoskeletal and connective tissue disorders     
Arthritis   19/220 (8.64%)  23 15/220 (6.82%)  18
Musculoskeletal joint pain, unspecified   165/220 (75.00%)  470 162/220 (73.64%)  472
Nervous system disorders     
HIV neuritis   36/220 (16.36%)  45 22/220 (10.00%)  24
post-herpetic neuralgia   7/220 (3.18%)  8 15/220 (6.82%)  20
Nervous system, other complaint   55/220 (25.00%)  76 46/220 (20.91%)  68
Reproductive system and breast disorders     
Pelvic inflammatory disease   21/220 (9.55%)  22 21/220 (9.55%)  24
Vaginal discharge   10/220 (4.55%)  10 14/220 (6.36%)  16
Genitourinary, other complaint   131/220 (59.55%)  280 140/220 (63.64%)  356
Respiratory, thoracic and mediastinal disorders     
Respiratory complaint, unspecified   98/220 (44.55%)  152 82/220 (37.27%)  132
Skin and subcutaneous tissue disorders     
Herpes zoster   4/220 (1.82%)  4 18/220 (8.18%)  18
Papulo-pruritic eruption (PPE)   15/220 (6.82%)  21 22/220 (10.00%)  27
Darkening nails   31/220 (14.09%)  32 32/220 (14.55%)  32
Rash, unspecified   118/220 (53.64%)  227 119/220 (54.09%)  201
Skin complaint, unspecified   123/220 (55.91%)  213 122/220 (55.45%)  212
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Steven Reynolds
Organization: NIAID
Phone: 256-772-220-087
Responsible Party: Steven Reynolds, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00405821     History of Changes
Other Study ID Numbers: 999907032
07-I-N032 ( Other Identifier: NIAID Intramural IRB )
First Submitted: November 29, 2006
First Posted: November 30, 2006
Results First Submitted: July 18, 2012
Results First Posted: September 28, 2012
Last Update Posted: September 28, 2012