Cervarix

Pharmacotherapeutic group: vaccines, papillomavirus vaccines, ATC code: J07BM02 Mechanism of action Cervarix is an adjuvanted, non-infectious recombinant vaccine prepared from highly purified virus-like particles (VLPs) of the major capsid L1 protein of the oncogenic HPV types 16 and 18.‍‍‍‍‍‍​​​‍​​​​​​ Because the VLPs contain no viral DNA, they cannot infect cells, replicate, or cause disease. Animal studies have shown that the efficacy of L1 VLP vaccines is largely mediated by the development of a humoral immune response. HPV-16 and HPV-18 are estimated to be responsible for approximately 70% of cervical cancers, 90% of anal cancers, 70% of HPV-related high-grade vulvar and vaginal intraepithelial neoplasia, and 78% of HPV-related high-grade anal intraepithelial neoplasia (AIN 2/3). Other oncogenic HPV types can also cause anogenital cancers (approximately 30%). HPV-45, -31, and -33 are the three most common non-vaccine HPV types identified in squamous cell cervical carcinoma (12.1%) and adenocarcinoma (8.5%). The term "premalignant anogenital lesions" in section 4.1 corresponds to high-grade cervical intraepithelial neoplasia (CIN 2/3), high-grade vulvar intraepithelial neoplasia (VIN 2/3), high-grade vaginal intraepithelial neoplasia (VaIN 2/3), and high-grade anal intraepithelial neoplasia (AIN 2/3). Clinical studies Clinical efficacy in women aged 15 to 25 years The efficacy of Cervarix was evaluated in two controlled, double-blind, randomised phase II and III clinical trials enrolling a total of 19,778 women aged 15 to 25 years. The phase II trial (study 001/007) enrolled only women who: - tested negative for oncogenic HPV DNA types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68; - were seronegative for HPV-16 and HPV-18; and - had normal cytology. The primary efficacy endpoint was incident HPV-16 and/or HPV-18 infection. Twelve-month persistent infection was evaluated as an additional efficacy endpoint. The phase III trial (study 008) enrolled women without prior screening for HPV infection, that is, regardless of baseline cytology and HPV serology and DNA status. The primary efficacy endpoint was CIN2+ associated with HPV-16 and/or HPV-18 (HPV-16/18). Cervical intraepithelial neoplasia (CIN) grades 2 and 3 (CIN 2/3) and cervical adenocarcinoma in situ (AIS) were used as surrogate markers of cervical cancer in clinical trials. Secondary endpoints included 6- and 12-month persistent infection. Infection persisting for at least 6 months has also been shown to be a relevant surrogate marker for cervical cancer in women aged 15 to 25 years. Prophylactic efficacy against HPV-16/18 infection in a population naïve to oncogenic HPV types Women (N = 1,113) were vaccinated in study 001, with efficacy assessed for up to 27 months. A pre-defined subgroup of women (N = 776) vaccinated in study 001 was followed in study 007 for up to 6.4 years (approximately 77 months) after first dose administration (median follow-up of 5.9 years). In the control group, five cases of 12-month persistent HPV-16/18 infection (4 HPV-16; 1 HPV-18) occurred, while one HPV-16 case occurred in the vaccine group in study 001. In study 007, the efficacy of Cervarix against 12-month persistent HPV-16/18 infection was 100% (95% CI: 80.5; 100). Sixteen cases of persistent HPV-16 infection and five cases of persistent HPV-18 infection were observed; all in the control group. In study HPV-023, subjects from the Brazilian cohort (N = 437) of study 001/007 were followed for a mean of 8.9 years (standard deviation 0.4 years) after the first dose. At study end in HPV-023, no cases of infection or histopathological lesions associated with HPV-16 or HPV-18 occurred in the vaccine group. In the placebo group, 4 cases of 6-month persistent infection and 1 case of 12-month persistent infection were observed. The study was not powered to demonstrate a difference between the vaccine and placebo groups for these endpoints. Prophylactic efficacy against HPV-16/18 in women naïve to HPV-16 and/or HPV-18 The primary efficacy analyses in study HPV-008 were performed in the according-to-protocol cohort (ATP cohort: includes women who received 3 doses of vaccine and were DNA negative and seronegative at month 0 and DNA negative at month 6 for the HPV type analysed). This cohort included women with normal cytology or low-grade cytology at study entry and excluded only women with high-grade cytology (0.5% of the overall population). Case counting started on day 1 after the third vaccine dose in the ATP cohort. Overall, 74% of enrolled women were naïve to both HPV-16 and HPV-18 (i.e., DNA negative and seronegative at study entry). Two analyses were performed in study HPV-008. The event-triggered analysis was conducted in the ATP cohort once at least 36 cases of HPV-16/18-associated CIN2+ had accrued. A second analysis was performed at study end. Vaccine efficacy against CIN2+ as the primary endpoint at study end is summarised in Table 1. In a supplementary analysis, the efficacy of Cervarix was evaluated against HPV-16/18-associated CIN3+ lesions. Table 1: Vaccine efficacy against high-grade cervical lesions associated with HPV-16/18 (ATP cohort) HPV-16/18 endpoint, ATP cohort(1), end-of-study analysis(3) Cervarix (N = 7,338); Control (N = 7,305); % efficacy (95% CI) n(2); n CIN2+: 5; 97; 94.9% (87.7; 98.4) CIN3+: 2; 24; 91.7% (66.6; 99.1) N = number of subjects in each group; n = number of cases. (1) ATP: includes women who received 3 doses of vaccine, were DNA negative and seronegative at month 0, and DNA negative at month 6 for the relevant HPV type (HPV-16 or HPV-18). (2) Includes 4 CIN2+ and 2 CIN3+ cases in which another oncogenic HPV type was identified in the lesion alongside HPV-16 or HPV-18. These cases were excluded from the type-assignment analysis (see below). (3) Mean follow-up was 40 months after dose 3. In the event-triggered analysis, efficacy was 92.9% (96.1% CI: 79.9; 98.3) against CIN2+ and 80% (96.1% CI: 0.3; 98.1) against CIN3+. In addition, statistically significant vaccine efficacy was demonstrated against CIN2+ individually associated with HPV-16 and HPV-18. Cases involving multiple HPV types were further investigated, with HPV typing performed by PCR (polymerase chain reaction) on at least one of the two preceding cytology samples. The aim was to perform a type-specific analysis of the HPV types already detected in the lesion, in order to identify the HPV types most likely to be causally responsible. This additional post-hoc analysis excluded cases (in both the vaccine and control groups) that did not have a causal link with HPV-16 or HPV-18 infections acquired during the trial. In this type-specific post-hoc analysis, 1 CIN2+ case occurred in the vaccine group versus 92 cases in the control group [efficacy 98.9% (95% CI: 93.8; 100)] and no CIN3+ cases occurred in the vaccine group versus 22 cases in the control group [efficacy 100% (95% CI: 81.8; 100)] at study end. In the event-triggered analysis, vaccine efficacy in the ATP cohort against HPV-16/18-related CIN1 was 94.1% (96.1% CI: 83.4; 98.5). Vaccine efficacy in the same cohort against HPV-16/18-related CIN1+ was 91.7% (96.1% CI: 82.4; 96.7). In the end-of-study analysis, vaccine efficacy in the ATP cohort against HPV-16/18-related CIN1 was 92.8% (95% CI: 87.1; 96.4). In the end-of-study analysis, 2 cases of HPV-16- or HPV-18-related VIN2+ or VaIN2+ were observed in the vaccine group and 7 in the control group within the ATP cohort. The study was not powered to demonstrate a difference between the vaccine and control groups for these endpoints. Vaccine efficacy in the ATP cohort against the virological endpoints (6- and 12-month persistent infection) associated with HPV-16/18 at study end is summarised in Table 2. Table 2: Vaccine efficacy against virological endpoints related to HPV-16/18 (ATP cohort) HPV-16/18 endpoint, ATP cohort(1), end-of-study analysis(2) Cervarix (N = 7,338); Control (N = 7,305); % efficacy (95% CI) n/N; n/N 6-month persistent infection: 35/7,182; 588/7,137; 94.3% (92.0; 96.1) 12-month persistent infection: 26/7,082; 354/7,038; 92.9% (89.4; 95.4) N = number of subjects in each group; n = number of cases. (1) ATP: includes women who received 3 doses of vaccine, were DNA negative and seronegative at month 0, and DNA negative at month 6 for the relevant HPV type (HPV-16 or HPV-18). (2) Mean follow-up was 40 months after dose 3. In the event-triggered analysis, efficacy was 94.3% (96.1% CI: 91.5; 96.3) against 6-month persistent infection and 91.4% (96.1% CI: 89.4; 95.4) against 12-month persistent infection. Efficacy against HPV types 16 and 18 in women with documented HPV-16 or HPV-18 infection at study entry There was no evidence of protection against disease caused by HPV types for which subjects were HPV DNA positive at study entry. However, individuals already infected with one of the vaccine HPV types prior to vaccination (HPV DNA positive) were protected against clinical disease caused by the other vaccine HPV type. Efficacy against HPV types 16 and 18 in women with or without prior infection or disease The total vaccinated cohort (TVC) included all subjects who received at least one dose of vaccine, regardless of their baseline HPV DNA status, cytology, and serological status. This cohort included women with or without current and/or prior HPV infection. Case counting started on day 1 after the first vaccine dose. Estimated efficacy is lower in the TVC, as the cohort includes women with pre-existing infection or lesions that would not be expected to be affected by Cervarix vaccination. The TVC may approximate the general population of women aged 15 to 25 years. Vaccine efficacy in the TVC against HPV-16/18-related high-grade cervical lesions at study end is summarised in Table 3. Table 3: Vaccine efficacy against high-grade cervical lesions associated with HPV-16/18 (TVC) HPV-16/18 endpoint, TVC(1), end-of-study analysis(2) Cervarix (N = 8,694); Control (N = 8,708); % efficacy (95% CI) n; n CIN2+: 90; 228; 60.7% (49.6; 69.5) CIN3+: 51; 94; 45.7% (22.9; 62.2) N = number of subjects in each group; n = number of cases. (1) TVC: includes all vaccinated subjects (who received at least one dose of vaccine) regardless of baseline HPV DNA status, cytology, and serological status. This cohort includes women with pre-existing infection/lesions. (2) Mean follow-up was 44 months after dose 1. Vaccine efficacy in the TVC against the virological endpoints (6- and 12-month persistent infection) associated with HPV-16/18 at study end is summarised in Table 4. Table 4: Vaccine efficacy against virological endpoints related to HPV-16/18 (TVC) HPV-16/18 endpoint, TVC(1), end-of-study analysis(2) Cervarix; Control; % efficacy (95% CI) n/N; n/N 6-month persistent infection: 504/8,863; 1,227/8,870; 60.9% (56.6; 64.8) 12-month persistent infection: 335/8,648; 767/8,671; 57.5% (51.7; 62.8) N = number of subjects in each group; n = number of cases. (1) TVC: includes all vaccinated subjects (who received at least one dose of vaccine) regardless of baseline HPV DNA status, cytology, and serological status. (2) Mean follow-up was 44 months after dose 1. Overall impact of vaccination on cervical HPV disease In study HPV-008, the incidence of high-grade cervical lesions was compared between the placebo and vaccine groups regardless of the HPV DNA type in the lesion. Vaccine efficacy against high-grade cervical lesions was assessed at study end in the TVC and TVC-naïve cohorts (Table 5). The TVC-naïve cohort is a subset of the TVC and includes women with normal cytology who were HPV DNA negative for 14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 at study entry. Table 5: Vaccine efficacy against high-grade cervical lesions regardless of HPV DNA type in the lesion, end-of-study analysis(3) Cervarix; Control; % efficacy (95% CI) N; cases; N; cases CIN2+ TVC-naïve(1): 5,466; 61; 5,452; 172; 64.9% (52.7; 74.2) TVC(2): 8,694; 287; 8,708; 428; 33.1% (22.2; 42.6) CIN3+ TVC-naïve(1): 5,466; 3; 5,452; 44; 93.2% (78.9; 98.7) TVC(2): 8,694; 86; 8,708; 158; 45.6% (28.8; 58.7) N = number of subjects in each group. (1) TVC-naïve: includes all vaccinated subjects (who received at least one dose of vaccine) with normal cytology who were HPV DNA negative for 14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 at entry. (2) TVC: includes all vaccinated subjects (who received at least one dose of vaccine) regardless of baseline HPV DNA status, cytology, and serological status. (3) Mean follow-up was 44 months after dose 1. In the end-of-study analysis, Cervarix reduced the need for definitive cervical therapeutic procedures (including loop electrosurgical excision procedure [LEEP], cold-knife conisation, and laser procedures) by 70.2% (95% CI: 57.8; 79.3) in the TVC-naïve population and by 33.2% (95% CI: 20.8; 43.7) in the TVC. Cross-protective efficacy The cross-protective efficacy of Cervarix against histopathological and virological endpoints (persistent infection) was evaluated in study HPV-008 for 12 non-vaccine oncogenic HPV types. The study was not powered to assess efficacy against disease caused by individual HPV types. Analysis of efficacy against the primary endpoint was confounded by multiple co-infections in CIN2+ lesions. In contrast to the histopathological endpoints, the virological endpoints were less affected by multiple infections. Consistent cross-protection against 6-month persistent infection and CIN2+ lesions was demonstrated for HPV types 31, 33, and 45 across all studied cohorts. Vaccine efficacy at study end against 6-month persistent infection and CIN2+ lesions associated with individual non-vaccine oncogenic HPV types is summarised in Table 6 (ATP cohort). Table 6: Vaccine efficacy against non-vaccine oncogenic HPV types, ATP(1) HPV type; 6-month persistent infection [Cervarix n; Control n; % efficacy (95% CI)]; CIN2+ [Cervarix n; Control n; % efficacy (95% CI)] HPV-16-related types (A9 species) HPV-31: 58; 247; 76.8% (69.0; 82.9) | 5; 40; 87.5% (68.3; 96.1) HPV-33: 65; 117; 44.8% (24.6; 59.9) | 13; 41; 68.3% (39.7; 84.4) HPV-35: 67; 56; -19.8% (<0.0; 17.2) | 3; 8; 62.5% (<0.0; 93.6) HPV-52: 346; 374; 8.3% (<0.0; 21.0) | 24; 33; 27.6% (<0.0; 59.1) HPV-58: 144; 122; -18.3% (<0.0; 7.7) | 15; 21; 28.5% (<0.0; 65.7) HPV-18-related types (A7 species) HPV-39: 175; 184; 4.8% (<0.0; 23.1) | 4; 16; 74.9% (22.3; 93.9) HPV-45: 24; 90; 73.6% (58.1; 83.9) | 2; 11; 81.9% (17.0; 98.1) HPV-59: 73; 68; -7.5% (<0.0; 23.8) | 1; 5; 80.0% (<0.0; 99.6) HPV-68: 165; 169; 2.6% (<0.0; 21.9) | 11; 15; 26.8% (<0.0; 69.6) Other types HPV-51: 349; 416; 16.6% (3.6; 27.9) | 21; 46; 54.4% (22.0; 74.2) HPV-56: 226; 215; -5.3% (<0.0; 13.1) | 7; 13; 46.1% (<0.0; 81.8) HPV-66: 211; 215; 2.3% (<0.0; 19.6) | 7; 16; 56.4% (<0.0; 84.8) n = number of cases. (1) ATP: includes women who received 3 doses of vaccine, were DNA negative and seronegative at month 0, and DNA negative at month 6 for the relevant HPV type. Confidence interval limits for vaccine efficacy were calculated. When the value 0 falls within the interval, i.e., the lower CI bound is < 0, efficacy is not considered statistically significant. Efficacy against CIN3 was demonstrated only for HPV-31, and protection against AIS was not established for any HPV type. Clinical efficacy in women aged 26 years and older The efficacy of Cervarix was assessed in a double-blind, randomised phase III trial (HPV-015) enrolling a total of 5,778 women aged 26–72 years (median: 37.0 years). The study was conducted in North America, Latin America, Asia, and Europe. The final analysis was performed at study end, 7 years after the first vaccination. The primary endpoint was a composite virological and histopathological measure: 6-month persistent infection associated with HPV-16/18 and/or CIN1+. The primary efficacy analyses were performed in the ATP and TVC cohorts, which included a subgroup of up to 15% of women with a history of HPV-related infection or disease (defined as two or more consecutive abnormal smears, abnormal colposcopies or biopsies, or treatment of the cervix following abnormal smears or colposcopic findings). Inclusion of this subgroup allowed assessment of prophylactic efficacy in a population likely to reflect real-world conditions, since adult women are the age group generally targeted by cervical screening. Vaccine efficacy at study end is summarised in the following table. There is no evidence as to whether prevention of persistent infection lasting at least 6 months is an adequate surrogate marker for the prevention of cervical cancer in women aged 26 years and older. Table 7 – Vaccine efficacy at study end in HPV-015 Endpoint; ATP(1) [Cervarix n/N; Control n/N; % efficacy (96.2% CI)]; TVC(2) [Cervarix n/N; Control n/N; % efficacy (96.2% CI)] HPV-16/18 6M PI and/or CIN1+: 7/1,852; 71/1,818; 90.5% (78.6; 96.5) | 93/2,768; 209/2,778; 56.8% (43.8; 67.0) 6M PI: 6/1,815; 67/1,786; 91.4% (79.4; 97.1) | 74/2,762; 180/2,775; 60% (46.4; 70.4) CIN2+: 1/1,852; 6/1,818; 83.7% (<0.0; 99.7) | 33/2,733; 51/2,735; 35.8% (<0.0; 61.0) ASC-US+: 3/1,852; 47/1,818; 93.8% (79.9; 98.9) | 38/2,727; 114/2,732; 67.3% (51.4; 78.5) 6M PI in subjects seropositive only at study entry: 3/851; 13/837; 78% (15.0; 96.4) | 42/1,211; 65/1,192; 38.7% (6.3; 60.4) Cross-protective efficacy HPV-31 6M PI: 10/2,073; 29/2,090; 65.8% (24.9; 85.8) | 51/2,762; 71/2,775; 29% (<0.0; 52.5) HPV-45 6M PI: 9/2,106; 30/2,088; 70.7% (34.2; 88.4) | 22/2,762; 60/2,775; 63.9% (38.6; 79.6) HPV-31 ASC-US+: 5/2,117; 23/2,127; 78.4% (39.1; 94.1) | 34/2,727; 55/2,732; 38.7% (2.0; 62.3) HPV-45 ASC-US+: 5/2,150; 23/2,125; 78.7% (40.1; 94.1) | 13/2,727; 38/2,732; 66.1% (32.7; 84.1) N = number of subjects in each group; n = number of subjects reporting at least one event in each group. 6M PI = 6-month persistent infection; CI = confidence interval; ASC-US = atypical squamous cells (abnormal cytology). (1) 3 doses of vaccine, DNA negative and seronegative at month 0 (unless stated otherwise) and DNA negative at month 6 for the relevant HPV type (HPV-16 and/or HPV-18). (2) At least one dose of vaccine, regardless of HPV DNA and serological status (unless stated otherwise) at month 0, including 15% of subjects with a prior history of HPV disease/infection. Efficacy against ≥ ASC-US (abnormal cytology) associated with non-vaccine oncogenic types was 37.2% (96.2% CI: 21.3; 50.1) (ATP). Efficacy against CIN1+ regardless of HPV type detected in the lesion was 22.9% (96.2% CI: 4.8; 37.7) (TVC). There is no evidence of protection against HPV-related disease in subjects aged 25 years and older who were DNA positive and/or had abnormal cytology at study entry. Immunogenicity Immune response following the primary vaccination schedule with Cervarix For HPV vaccines, no minimum antibody level associated with protection against CIN grade 2 or 3 or against persistent infection associated with the vaccine HPV types has been defined. The antibody response to HPV-16 and HPV-18 was measured directly using a type-specific ELISA assay (version 2, MedImmune methodology, modified by GSK), which correlates with a pseudovirion-based neutralisation assay (PBNA). Immunogenicity induced by three doses of Cervarix was evaluated in 5,465 females aged 9 to 55 years and in more than 800 males aged 10 to 18 years. In clinical trials, more than 99% of initially seronegative subjects had seroconverted for both HPV types 16 and 18 one month after the third dose. Vaccine-induced IgG geometric mean titres (GMTs) were clearly above titres observed in women previously infected but who had cleared the HPV infection (natural infection). Initially seropositive and seronegative subjects achieved similar titres after vaccination. Persistence of immune response following Cervarix vaccination In study 001/007, which enrolled women aged 15 to 25 years at the time of vaccination, the immune response against HPV-16 and HPV-18 was evaluated for up to 76 months after the first dose. In study 023 (a sub-study of 001/007), the immune response was continuously evaluated up to 113 months. Ninety-two subjects in the vaccine group had immunogenicity data over the [M107–M113] interval after the first dose, with a median follow-up of 8.9 years. All subjects (100%; 95% CI: 96.1; 100) remained seropositive for HPV-16 and HPV-18 by ELISA. Vaccine-induced IgG GMTs for both HPV-16 and HPV-18 peaked at month 7 and then declined to a plateau from month 18 onwards through the [M107–M113] interval. ELISA GMTs for both HPV-16 and HPV-18 remained at least 10-fold higher than the ELISA GMTs observed in women who had cleared a natural HPV infection. In study 008, immunogenicity up to month 48 was similar to the response observed in study 001. A similar kinetic profile was observed for neutralising antibodies. In another clinical trial (study 014) conducted in women aged 15 to 55 years, all subjects seroconverted for both HPV types 16 and 18 after the third dose (at month 7). However, GMTs were lower in women older than 25 years. Of 470 subjects (142 aged 15–25 years, 172 aged 26–45 years, and 156 aged 46–55 years) who completed study HPV-014 and received the 3-dose schedule, follow-up continued in the extension study HPV-060 for up to 10 years. Ten years after the first dose, 100% of subjects in the 15–25-year age group, 99.2% in the 26–45-year group, and 96.3% in the 46–55-year group remained seropositive for HPV-16, and 99.2%, 93.7%, and 83.8%, respectively, for HPV-18. Across all age groups, GMTs remained at least 5- to 32-fold higher for HPV-16 and 3- to 14-fold higher for HPV-18 than those observed in women who had cleared a natural infection for both antigens. Evidence of an anamnestic (immune memory) response In study 024 (a subset of 001/007), a challenge dose of Cervarix was administered to 65 subjects at a mean interval of 6.8 years after the first vaccine dose. An anamnestic immune response to HPV-16 and HPV-18 (assessed by ELISA) was observed at 1 week and 1 month after the challenge dose. GMTs one month post-challenge exceeded those observed one month after the primary 3-dose vaccination schedule. Bridging Cervarix efficacy from young adult women to adolescents In pooled analyses (HPV-029, -30, and -48), 99.7% of girls aged 9 years seroconverted for HPV type 16 and 100% for HPV type 18; importantly, seroconversion after the third dose (at month 7) yielded GMTs at least 1.4-fold and 2.4-fold higher than in girls aged 10 to 14 years and adolescents and women aged 15 to 25 years, respectively. In two clinical trials (HPV-012 and -013) conducted in girls aged 10 to 14 years, all subjects seroconverted for both HPV types 16 and 18 after the third dose (at month 7), with GMTs at least 2-fold higher than in women aged 15 to 25 years. In clinical studies (HPV-070 and HPV-048) conducted in girls aged 9 to 14 years who received a 2-dose schedule (month 0, 6 or month 0, 12) and in young women aged 15–25 years who received Cervarix according to the standard month 0, 1, 6 schedule, all subjects seroconverted for both HPV types 16 and 18 one month after the second dose. The immune response after 2 doses in girls aged 9 to 14 years was non-inferior to the response after 3 doses in women aged 15 to 25 years. On the basis of these immunogenicity data, efficacy of Cervarix is inferred for ages 9 to 14 years. Duration of immune response in women aged 26 years and older In the phase III trial (HPV-015) in women aged 26 years and older, all subjects seroconverted one month after the third dose. At month 84, that is, 78 months after completion of the full vaccination schedule, 99.3% and 95.9% of initially seronegative women remained seropositive for anti-HPV-16 and anti-HPV-18 antibodies, respectively. All initially seropositive women remained seropositive for both anti-HPV-16 and anti-HPV-18 antibodies. Antibody titres peaked at month 7, then gradually declined and stabilised at levels maintained through month 84. Immunogenicity in males aged 10 to 18 years Immunogenicity in males was assessed in 2 clinical studies, HPV-011 (N = 173) and HPV-040 (N = 556). The data showed comparable immunogenicity in males and females. In study HPV-011, seroconversion in all subjects for both HPV-16 and -18 and the GMT levels were non-inferior to those observed in women aged 15 to 25 years in study HPV-012. Bridging clinical efficacy against anal lesions and cancers No efficacy study against anal premalignant lesions has been conducted with Cervarix. However, studies conducted in girls aged 9 to 14 years (study HPV-071) and in women aged 18 to 45 years (study HPV-010) consistently demonstrated a higher immune response with Cervarix than with the comparator, for which data on efficacy against anal premalignant lesions are convincing and protection has been demonstrated. Immunogenicity in women infected with HIV Two clinical studies evaluated the safety and immunogenicity of Cervarix: Clinical study HPV-020, conducted in South Africa, vaccinated 22 HIV-uninfected and 42 HIV-infected subjects (WHO clinical stage 1; ATP cohort for immunogenicity) with Cervarix. Study HPV-019, a comparative study of Cervarix and a quadrivalent HPV vaccine, was conducted in 289 (ATP cohort = 157) HIV-uninfected and 257 (ATP cohort = 166) HIV-infected women aged 15–25 years in Brazil, Estonia, India, and Thailand. At study entry, HIV-infected subjects in both studies had to be asymptomatic regardless of their prior clinical stage; have an undetectable viral load (i.e., viral load < 400 copies/mL) for at least 6 months if on antiretroviral therapy (ART) (HPV-020) or on highly active antiretroviral therapy (HAART) for at least 1 year (HPV-019); not have been diagnosed with active tuberculosis (TB) or be on TB treatment; and, in study HPV-019 only, have a CD4 cell count > 350 cells/mm³. In both studies, seroconversion (at month 7) in HIV-infected subjects given Cervarix in the ATP cohort was 100% for both antigens. In study HPV-019, seropositivity at month 24 after Cervarix vaccination was 100% for HPV-16 antibodies and > 96% for HPV-18 antibodies, with a geometric mean concentration (GMC) more than 12-fold higher than the response to natural HPV infection. In both studies, antibody GMCs in HIV-infected subjects were lower than in HIV-negative subjects (non-overlapping 95% confidence intervals). In study HPV-019, at month 7, Cervarix demonstrated superior immune responses (GMC ratio of neutralising antibodies) for both HPV-16 and HPV-18 antigens in HIV-infected subjects compared with the quadrivalent HPV vaccine. The clinical relevance of this observation is unclear. No clinical data on efficacy or on protection against persistent infection or precancerous lesions in HIV-infected women are available. The reactogenicity and safety profile of Cervarix observed in HIV-infected women was consistent with the known safety profile in healthy subjects (see section 4.8).