Trial Outcomes & Findings for Quadrivalent HPV Vaccine to Prevent Anal HPV in HIV-infected Men and Women (NCT NCT01461096)

Last Updated: 2021-11-02

Results Overview

The outcome for this evaluation was time to the first new persistent infection of any of HPV 6, 11, 16, or 18. Persistent infection was defined as an infection confirmed by positive anal HPV PCR results at 2 consecutive visits at least 16 weeks apart without an intervening negative result. A participant who had a positive measurement on his/her last measurement with no consecutive confirmatory measurement was considered as having a persistent infection. Participants with pre-existing HPV infection at baseline were evaluable for the primary outcome if they were PCR negative for at least one of the four vaccine HPV types at baseline. NOTE: Use 5th and 10th percentiles in years from baseline to the first new persistent infection as the summary measure.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

575 participants

Primary outcome timeframe

From baseline to participant's last study visit, for up to 4 years

Results posted on

2021-11-02

Participant Flow

In less than 18 months, the full study cohort of 575 participants (472 males and 103 females) were enrolled and randomized in A5298. The first participant was randomized on March 8, 2012 and the last was randomized on August 23, 2013.

Participant milestones

Participant milestones
Measure	Quadrivalent HPV Vaccine Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Overall Study STARTED	288	287
Overall Study Did Not Start Treatment	0	1
Overall Study COMPLETED	226	226
Overall Study NOT COMPLETED	62	61

Reasons for withdrawal

Reasons for withdrawal
Measure	Quadrivalent HPV Vaccine Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Overall Study Death	3	6
Overall Study Severe debilitation, unable to continue	1	1
Overall Study Subj not able to get to clinic	15	13
Overall Study Site is closing	27	30
Overall Study Withdrawal by Subject	5	3
Overall Study Subj not willing to adhere to reqs	3	4
Overall Study Lost to Follow-up	8	4

Baseline Characteristics

Row population differs from the overall due to Missing

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Quadrivalent HPV Vaccine n=288 Participants Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine n=287 Participants Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Total n=575 Participants Total of all reporting groups
Age, Continuous	47 years n=288 Participants	48 years n=287 Participants	47 years n=575 Participants
Sex: Female, Male Female	52 Participants n=288 Participants	51 Participants n=287 Participants	103 Participants n=575 Participants
Sex: Female, Male Male	236 Participants n=288 Participants	236 Participants n=287 Participants	472 Participants n=575 Participants
Race/Ethnicity, Customized White Non-Hispanic	125 Participants n=288 Participants	136 Participants n=287 Participants	261 Participants n=575 Participants
Race/Ethnicity, Customized Black Non-Hispanic	91 Participants n=288 Participants	89 Participants n=287 Participants	180 Participants n=575 Participants
Race/Ethnicity, Customized Hispanic (Regardless of Race)	63 Participants n=288 Participants	54 Participants n=287 Participants	117 Participants n=575 Participants
Race/Ethnicity, Customized Asian, Pacific Islander	5 Participants n=288 Participants	7 Participants n=287 Participants	12 Participants n=575 Participants
Race/Ethnicity, Customized American Indian, Alaskan Native	2 Participants n=288 Participants	0 Participants n=287 Participants	2 Participants n=575 Participants
Race/Ethnicity, Customized More than one race	2 Participants n=288 Participants	1 Participants n=287 Participants	3 Participants n=575 Participants
Presence of HGAIN at entry HGAIN	95 Participants n=288 Participants	92 Participants n=287 Participants	187 Participants n=575 Participants
Presence of HGAIN at entry No HGAIN	193 Participants n=288 Participants	195 Participants n=287 Participants	388 Participants n=575 Participants
IV drug history Never	270 Participants n=288 Participants	259 Participants n=287 Participants	529 Participants n=575 Participants
IV drug history Previously	18 Participants n=288 Participants	28 Participants n=287 Participants	46 Participants n=575 Participants
HIV RNA results (copies/mL) <50	226 Participants n=288 Participants	244 Participants n=287 Participants	470 Participants n=575 Participants
HIV RNA results (copies/mL) 50-<200	23 Participants n=288 Participants	15 Participants n=287 Participants	38 Participants n=575 Participants
HIV RNA results (copies/mL) 200-<500	13 Participants n=288 Participants	4 Participants n=287 Participants	17 Participants n=575 Participants
HIV RNA results (copies/mL) 500-<1000	3 Participants n=288 Participants	4 Participants n=287 Participants	7 Participants n=575 Participants
HIV RNA results (copies/mL) 1000-<10000	10 Participants n=288 Participants	6 Participants n=287 Participants	16 Participants n=575 Participants
HIV RNA results (copies/mL) >=10000	7 Participants n=288 Participants	9 Participants n=287 Participants	16 Participants n=575 Participants
HIV RNA results (copies/mL) Missing	6 Participants n=288 Participants	5 Participants n=287 Participants	11 Participants n=575 Participants
Lowest documented CD4 count	254 cells/mm^3 n=260 Participants • Row population differs from the overall due to Missing	259 cells/mm^3 n=255 Participants • Row population differs from the overall due to Missing	255 cells/mm^3 n=515 Participants • Row population differs from the overall due to Missing
Absolute CD4 count	598 cells/mm^3 n=285 Participants • Row population differs from the overall due to Missing	614 cells/mm^3 n=284 Participants • Row population differs from the overall due to Missing	602 cells/mm^3 n=569 Participants • Row population differs from the overall due to Missing
Percent CD4	32 % n=285 Participants • Row population differs from the overall due to Missing	31 % n=284 Participants • Row population differs from the overall due to Missing	31.70 % n=569 Participants • Row population differs from the overall due to Missing

PRIMARY outcome

Timeframe: From baseline to participant's last study visit, for up to 4 years

Population: The efficacy analysis for persistent anal HPV employed a modified intent-to-treat (mITT) approach wherein all participants who received at least one dose of vaccine and all first new persistent infections that began after the first vaccination were included.

Outcome measures

Outcome measures
Measure	Quadrivalent HPV Vaccine n=286 Participants Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine n=283 Participants Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Time to the First New Persistent Infection of HPV 6, 11, 16, or 18 5th percentile	1.90 Years Interval 0.94 to 2.46	1.04 Years Interval 0.52 to 2.05
Time to the First New Persistent Infection of HPV 6, 11, 16, or 18 10th percentile	2.92 Years Interval 2.46 to Not estimable as the upper limit for survival function at all years was above 90%.	2.05 Years Interval 1.94 to 2.95

SECONDARY outcome

Timeframe: From Week 52 to participant's last study visit, for up to 4 years

Population: mITT population including all participants who received at least one dose of vaccine.

HGAIN was defined as AIN2 (moderate dysplasia, with no mention of AIN grade III), AIN3 (severe dysplasia, carcinoma in-situ, or AIN grade II/III), high grade AIN not specified, or adenocarcinoma in situ found in the intra-anal or perianal region.

Outcome measures

Outcome measures
Measure	Quadrivalent HPV Vaccine n=288 Participants Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine n=286 Participants Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Number of Participants With Biopsy-proven High-grade Anal Intraepithelial Neoplasia (HGAIN) Occurrences and Reoccurrences After Week 52	46 Participants	45 Participants

SECONDARY outcome

Timeframe: At baseline, Week 52, Week 104 and Week 156

Population: mITT population including all participants who received at least one dose of vaccine.

Anal cytologic abnormalities include: atypical squamous cells undetermined significance (ASCUS), atypical squamous cells favor high-grade SIL/squamous cell carcinoma (ASC-H), low-grade squamous intraepithelial lesion/mild dysplasia/HPV (LSIL), or high-grade SIL/moderate dysplasia to severe dysplasia/carcinoma in situ/features of invasion (HSIL).

Outcome measures

Outcome measures
Measure	Quadrivalent HPV Vaccine n=288 Participants Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine n=286 Participants Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Number of Participants With Anal Cytological Abnormality Occurrences Abnormal cytology at Week 156 visit	58 Participants	72 Participants
Number of Participants With Anal Cytological Abnormality Occurrences Abnormal cytology at baseline	182 Participants	188 Participants
Number of Participants With Anal Cytological Abnormality Occurrences Abnormal cytology at Week 52 visit	123 Participants	121 Participants
Number of Participants With Anal Cytological Abnormality Occurrences Abnormal cytology at Week 104 visit	98 Participants	108 Participants

SECONDARY outcome

Timeframe: From baseline to participant's last study visit, for up to 4 years

Population: mITT population including all participants who received at least one dose of vaccine.

To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, august 2009).

Outcome measures

Outcome measures
Measure	Quadrivalent HPV Vaccine n=288 Participants Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine n=286 Participants Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Number of Participants With Grade 3 or 4 Adverse Events (AEs) That Were Possibly, Probably, or Definitely Related to the Vaccine, as Determined by the Local Investigator	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline to participant's last study visit, for up to 4 years

Population: mITT population wherein all participants who received at least one dose of vaccine and all first new persistent infections that began after the first vaccination were included.

The outcome for this evaluation was time to the first new persistent infection of any of oral HPV 6, 11, 16, or 18. Persistent infection was defined as an infection confirmed by positive oral HPV PCR results at 2 consecutive visits at least 16 weeks apart without an intervening negative result. A participant who had a positive measurement on his/her last measurement with no consecutive confirmatory measurement was considered as having a persistent infection. Participants with pre-existing HPV infection at baseline were evaluable for the primary endpoint if they were PCR negative for at least one of the four vaccine HPV types at baseline. NOTE: Use 5th and 10th percentiles in years from baseline to the first new persistent infection as the summary measure.

Outcome measures

Outcome measures
Measure	Quadrivalent HPV Vaccine n=288 Participants Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo Vaccine n=286 Participants Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Time to First New Persistent Oral HPV Infection of Vaccine Types Detected From Oral Rinse 5th percentile	NA Years Interval 2.99 to Not estimable as the estimate for survival function at all years was above 95%. (Note: A total of 7 events were observed, and the 3-year persistent infection free rate was about 0.97.)	NA Years Interval 1.9 to Not estimable as the estimate for survival function at all years was above 95%. (Note: A total of 10 events were observed, and the 3-year persistent infection free rate was about 0.96.)
Time to First New Persistent Oral HPV Infection of Vaccine Types Detected From Oral Rinse 10th percentile	NA Years Not estimable as the estimate for survival function at all years was above 90%.	NA Years Not estimable as the estimate for survival function at all years was above 90%.

Adverse Events

qHPV

Serious events: 33 serious events

Other events: 87 other events

Deaths: 3 deaths

Placebo

Serious events: 46 serious events

Other events: 95 other events

Deaths: 6 deaths

Serious adverse events

Other adverse events

Additional Information

ACTG Clinicaltrials.gov Coordinator

ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

Phone: (301) 628-3313

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights
Publication restrictions are in place

Restriction type: OTHER

Measure	qHPV n=288 participants at risk Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. Quadrivalent HPV Vaccine: Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.	Placebo n=287 participants at risk Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. Placebo Vaccine for Male Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24. Placebo Vaccine for Female Participants Only: Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
Gastrointestinal disorders Abdominal pain	4.5% 13/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	5.6% 16/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Gastrointestinal disorders Anogenital dysplasia	3.8% 11/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	7.0% 20/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Gastrointestinal disorders Diarrhoea	5.6% 16/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	9.1% 26/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Gastrointestinal disorders Nausea	5.6% 16/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	7.0% 20/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Gastrointestinal disorders Vomiting	2.4% 7/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	7.0% 20/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
General disorders Chills	7.3% 21/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	5.9% 17/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
General disorders Fatigue	6.2% 18/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	6.6% 19/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
General disorders Pyrexia	10.8% 31/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	10.5% 30/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Musculoskeletal and connective tissue disorders Arthralgia	4.9% 14/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	6.3% 18/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Musculoskeletal and connective tissue disorders Pain in extremity	7.6% 22/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	6.6% 19/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Nervous system disorders Headache	5.6% 16/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	5.9% 17/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Respiratory, thoracic and mediastinal disorders Cough	11.5% 33/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	7.7% 22/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.6% 19/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	7.0% 20/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Respiratory, thoracic and mediastinal disorders Nasal congestion	6.2% 18/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	4.9% 14/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.6% 19/288 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.	3.5% 10/287 • From baseline to participant's last study visit, for up to 4 years At entry, the protocol required reporting of signs/symptoms \>=Grade 3 that occurred within 14 days before entry. After entry, the protocol required reporting of signs/symptoms \>=Grade 3, laboratory results \>=Grade 3 and events that led to a change in treatment, regardless of grade. HGB, PLT, ANC, AST, ALT, INR, total and direct bilirubin, creatinine were reported regardless of grade. The DAIDS AE Grading Table (V1.0) and Expedited AE Manual (V2.0) were used.