Impact of age at vaccination and cervical HPV infection status on binding and neutralizing antibody titers at 10 years after receiving single or higher doses of quadrivalent HPV vaccine.

Long-term follow-up of a cohort of unmarried girls who received one, two, or three doses of quadrivalent HPV vaccine, between 10 and 18 years of age, in an Indian multi-centric study allowed us to compare antibody responses between the younger and older age cohorts at 10-years post-vaccination, and study the impact of initiation of sexual activity and cervical HPV infections on antibody levels. Among the younger (10-14 years) recipients of a single dose, 97.7% and 98.2% had detectable binding antibody titers against HPV 16 and HPV 18 respectively at ten years post-vaccination. The proportions among those receiving a single dose at age 15-18 years were 92.3% and 94.2% against HPV 16 and HPV 18 respectively. Mean HPV 16 binding antibody titers were 2.1 folds (95%CI 1.4 to 3.3) higher in those vaccinated at ages 10-14 years, and 1.9 folds (95%CI 1.2 to 3.0) higher in those vaccinated at 15-18 years compared to mean titers seen in the unvaccinated women. Compared to previous timepoints of 36 or 48 months, binding antibodies against HPV 16 and neutralizing antibodies against both HPV 16 and HPV 18 were significantly higher at 10 years. This rise was more pronounced in participants vaccinated at 15-18 years. No association of marital status or cervical HPV infections was observed with the rise in titer. Durability of antibody response in single dose recipients correlated well with the high efficacy of a single dose against persistent HPV 16/18 infections irrespective of age at vaccination, as we reported earlier.

Evaluation of immune response to single dose of quadrivalent HPV vaccine at 10-year post-vaccination.

BACKGROUND: The recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women. METHODS: Participants received at age 10-18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women. RESULTS: The dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios < 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination. CONCLUSION: Our study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination.

Impact of HPV vaccination on HPV-related oral infections.

BACKGROUND: Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. Although the efficacy of the HPV vaccine in preventing the development of cervical pre-malignant lesions has been well demonstrated, the efficacy of the HPV vaccine in preventing HPV infection in the upper respiratory tract has been poorly studied. METHODS: In the context of the IARC cohort study of two versus three doses of HPV vaccine in India, we compared the HPV type prevalence in the oral cavity of women vaccinated with three doses, two doses, or a single dose of quadrivalent HPV vaccine with that of unvaccinated women. A total of 997 oral samples, from 818 vaccinated women and 179 unvaccinated women, were collected at three study sites. All the participants were sexually active at the time of sample collection. RESULTS: The age-standardized proportion (ASP) of HPV16/18 infections was 2.0 % (95 % CI, 1.0-3.0 %) in vaccinated women and 4.2 % (95 % CI, 1.2-7.2 %) in unvaccinated women. HPV16 was detected in 3.5 % of single-dose recipients, 1.2 % of two-dose recipients (days 1 and 180), and 1.5 % of three-dose recipients (days 1, 60, and 180), whereas 3.3 % of the unvaccinated women tested positive for HPV16. The same trend was observed for HPV18. DISCUSSION: Our findings agree with those of previous studies on the efficacy of HPV vaccination in reducing oral HPV infections and provide indications that a single vaccine dose may be less efficient than two or three doses in preventing oral HPV infection.

Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study.

BACKGROUND: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination. METHODS: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702. FINDINGS: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed). INTERPRETATION: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses. FUNDING: Bill & Melinda Gates Foundation.

Acquisition, prevalence and clearance of type-specific human papillomavirus infections in young sexually active Indian women: A community-based multicentric cohort study.

In context of the ongoing multi-centric HPV vaccine study in India, unvaccinated married women (N = 1484) aged 18-23 years were recruited in 2012-2015 as age-matched controls to the vaccinated women and followed up yearly. We assess type-specific prevalence, natural history and potential determinants of human papillomavirus (HPV) infection in these unvaccinated women. Cervical samples were collected yearly for at least four consecutive years. A Multiplex Type-Specific E7-Based polymerase chain reaction assay was used to detect 21 HPV types. HPV prevalence was 36.4% during 6 years. Most common HPV types were 16 (6.5%) and 31 (6.1%). Highest persistence were observed for HPV 35 (62.5%) and 52 (25%). New HPV acquisition rate was 5.6/1000 person-months of observation (PMO), highest for HPV 16 (1.1/1000 PMO). Type-specific clearance rates ranged between 2.9-5.5/100 PMO. HPV 16 and/or 18 infections were 41% (95% CI 4-63%) lower among women with 2-<3 years between marriage and first cervical sample collection compared to those with <2 years. HPV prevalence and acquisition rates in young Indian women were lower than their Western counterparts. HPV 16 infections being most common shows the importance and potential impact of HPV vaccination in India. Women with 2-3 years exposure had reduced risk possibly due to higher infections clearance.

Two-dose recommendation for Human Papillomavirus vaccine can be extended up to 18 years - updated evidence from Indian follow-up cohort study.

Earlier publication from the ongoing multi-centric study of the International Agency for Research on Cancer to evaluate less than three doses of the quadrivalent Human Papillomavirus (HPV) vaccine in India amongst unmarried girls demonstrated non-inferior total antibody titres, neutralizing antibody titres and antibody avidity in 2-dose recipients compared to 3-dose recipients at 15-18 years of age (Bhatla et al., 2018) [7]. The number of participants recruited at 15-18 years of age was 1515 and 1795 in the 3-dose and the 2-dose groups respectively. At a median follow-up of 7 years, incident HPV 16/18 infections were detected in 1.6% women receiving two doses and 0.8% women receiving three doses at 15-18 years. Frequency of incident infection was 7.0% in the age- and site-matched unvaccinated women (N = 1484). No persistent infection from HPV 16 was observed in the 2- or 3-dose recipients and one (0.2%) persistent HPV 18 infection was documented, each in the 3-dose and 2-dose cohorts. Among the unvaccinated women, the frequency of HPV 16/18 persistent infection was 1.7%. The protection offered by two doses of quadrivalent HPV vaccine against incident and persistent infections in recipients at 15-18 years is comparable to that seen in 3-dose recipients at 15-18 years.

Are two doses of human papillomavirus vaccine sufficient for girls aged 15-18 years? Results from a cohort study in India.

Extending two-dose recommendations of HPV vaccine to girls between 15 and 18 years will reduce program cost and improve compliance. Immunogenicity and vaccine targeted HPV infection outcomes were compared between 1795 girls aged 15-18 years receiving two (1-180 days) and 1515 girls of same age receiving three (1-60-180 days) doses. Immunogenicity outcomes in 15-18 year old two-dose recipients were also compared with the 10-14 year old three-dose (N = 2833) and two-dose (N = 3184) recipients. The 15-18 year old two-dose recipients had non-inferior L1-binding antibody titres at seven months against vaccine-targeted HPV types compared to three-dose recipients at 15-18 years and three-dose recipients at 10-14 years of age. Neutralizing antibody titres at 18 months in 15-18 year old two-dose recipients were non-inferior to same age three-dose recipients for all except HPV 18. The titres were inferior to those in the 10-14 year old three-dose recipients for all targeted types. Frequency of incident infections from vaccine-targeted HPV types in the 15-18 year old two-dose recipients was similar to the three dose recipients. None of the girls receiving two or three doses had persistent infection from vaccine-targeted types. These findings support that two doses of HPV vaccine can be extended to girls aged 15-18 years.

Improved Survival of Cervical Cancer Patients in a Screened Population in Rural India

Objectives: To describe the survival experience of cervix cancer patients in a screened rural population in India. Methods: Included 558 cervical cancer patients diagnosed in 2000-2013 in a cohort of 100,258 women invited for screening during 2000-2003. The primary end point was death from cervical cancer. We used the Kaplan-Meier method to estimate cumulative observed survival and Cox proportional hazards regression to assess the effect of patient characteristics on survival after diagnosis. Results: Of the 558 cases included, 143 (26%) and 114 (20%) were diagnosed in stages IA and IB respectively; 252 (45.2%) were dead, and 306 (54.8%) were alive at the last follow-up. The overall 5-year observed survival was 60.5%. The 5-year survival of stage IA patients was 95.1% and 5.3% for stage IV patients. All surgically treated stage IA patients, 94.1% of stage IB patients receiving intracavitary radiotherapy, 62% of stage IIB, 49% of stage III and 25% of stage IV patients receiving radiotherapy survived for 5 years. Conclusion: Higher 5-year survival in our study than elsewhere in India is due to the high proportion of early stage cancers detected by screening combined with adequate treatment, resulting into a favourable prognosis.

Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study.

BACKGROUND: An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study. METHODS: Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10-18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. FINDINGS: Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 [95% CI 1·02-1·23] and for HPV 18 1·04 [0·92-1·19]) at 7 months, but was inferior in the two-dose default (0·33 [0·29-0·38] for HPV 16 and 0·51 [0·43-0·59] for HPV 18) and one-dose default (0·09 [0·08-0·11] for HPV 16 and 0·12 [0·10-0·14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2-5·1). INTERPRETATION: Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment. FUNDING: Bill & Melinda Gates Foundation.

Response to article titled "US-funded measurements of cervical cancer death rates in India: scientific and ethical concerns" by Eric J Suba.

Dr Eric Suba has been distorting facts and persistently disseminating biased and misleading views and statements regarding our studies over the past several years. His article in the Indian Journal of Medical Ethics fails to mention the facts that seem unfavourable to his arguments, and the ethical concerns are unsubstantiated by the evidence. In this context, we present the following clarifications for the attention of your readers, notably with regard to: (i) the study design and inclusion of a control group; (ii) the informed consent of the women participating in the study; (iii) the conformity with international ethical standards and guidelines, and (iv) the provision of screening to women in the control arm of the studies. We also highlight the benefits that are flowing from this research and the risk that misinformation may further delay access for women to life-saving cervical cancer screening.

Evaluation of cytology and visual triage of human papillomavirus-positive women in cervical cancer prevention in India.

Although virtually all cervical cancers and most cervical intraepithelial neoplasia (CIN) are caused by persistent human papillomavirus (HPV) infection, only a small proportion of HPV-positive women have or will develop CIN. Triaging HPV-positive women has been suggested to reduce the false-positive rate and proportion of women referred for CIN confirmation and/or treatment. In two cross-sectional studies and one randomized trial in India, we evaluated the impact of using cytology or visual inspection with acetic acid (VIA) to triage HPV-positive women on the proportion of women who would be referred for CIN confirmation and on the detection rates of high-grade CIN. We present the numbers of HPV test-positive women found and the CIN detected among them. We further assess the proportions that would be referred for CIN confirmation with colposcopy/biopsy and CIN that would be detected if cytology triage or VIA triage were used. Using cytology triage at atypical squamous cells of undetermined significance threshold or VIA triage reduced referrals for colposcopy by about 62% and 59%, respectively (p-value = 0.012), but missed around 16% and 18%, respectively, of the high-grade CIN (p-value = 0.539) indicating similar performance of both triaging approaches. The choice of a triage test in different low- and middle-income countries (LMIC) would depend on the availability and affordability in the particular setting. Cytology triage may be considered in settings where adequate infrastructure exists, whereas VIA triage may be suitable in settings with limited or no cytology infrastructure.

Accuracy of concurrent visual and cytology screening in detecting cervical cancer precursors in rural India.

The high burden of cervical cancer and inadequate/suboptimal cytology screening in developing countries led to the evaluation of visual screening tests, like visual inspection with acetic acid (VIA) and Lugol's iodine (VILI). We describe the performance of VIA, VILI and cytology, carried out in a multinational project called "Screening Technologies to Advance Rapid Testing" in 5,519 women aged 30-49 years, in detecting cervical intraepithelial neoplasia (CIN). VIA, VILI and cytology were positive in 16.9%, 15.6% and 6.1% women, respectively. We found 57 cases of CIN2, 55 of CIN3 and 12 of cervical cancer; 90% of CIN3 and 43% CIN2 cases were positive for p16 overexpression and high-risk HPV infection, indicating a high validity of histological diagnosis. The sensitivity of VIA, VILI and cytology to detect high-grade CIN were 64.5%, 64.5% and 67.7%, respectively; specificities were 84.2%, 85.5% and 95.4%. A high proportion of p16 positive CIN 3 (93.8%) and 2 (76.9%) were positive on cytology compared with visual tests (68.8% and 53.8%, respectively) indicating a higher sensitivity of cytology to detect p16 positive high-grade CIN. However, the immediate availability of the results from the visual tests permits diagnosis and/or treatment to be performed in the same sitting, which can potentially reduce loss to follow-up when women must be recalled following positive cytology. Organizing visual screening services in low-resource countries may facilitate the gradual building of an infrastructure committed to screening allowing the eventual introduction of more sensitive, highly objective, reproducible and affordable human papillomavirus screening tests in future.

Prevalence of human papillomavirus types in cervical lesions from women in rural Western India.

Cervical cancer is the most common cancer among women in many areas of India which contributes for a fifth of the global burden of disease. Persistent infection with one of the high-risk human papillomaviruses (HPV) has been established as the cause for cervical cancer and the documentation of the prevalence of HPV types in cervical cancer in different regions of India is useful for a prevention program combining both screening and vaccination. In this study, the HPV type distribution and the frequency of p16(INK4a) immunoexpression have been determined in 125 cases of inflammatory lesions or grade 1 cervical intraepithelial neoplasia, 74 cases of grade 2, 72 cases of grade 3, and 113 cervical cancer cases diagnosed among women from rural Solapur and Osmanabad districts, Maharashtra. The overall prevalence of high-risk HPV was 37.6% in inflammatory lesions or grade 1 cervical intraepithelial neoplasia, 63.5% in grade 2, 97.2% in grade 3 and 92% in cervical cancer cases. HPV 16 and HPV 18 were detected in 80.6% of grade 3 cervical intraepithelial neoplasia and 86.5% of cervical cancer cases. 94.7% of the cervical cancer and 84.4% of the high grade lesions with a strong and full thickness staining for p16(INK4a) were positive for HPV infection; p16(INK4a) immunoexpression increased with worsening grade of cervical intraepithelial neoplasia. The HPV genotyping data showing a high HPV 16 and 18 prevalence in cancer specimens indicate that prophylactic HPV 16/18 vaccination would have a significant impact on the prevention of cervical cancer in India.

Prevalence and determinants of high-risk human papillomavirus infection in middle-aged Indian women.

BACKGROUND: Little is known about the prevalence and determinants of human papillomavirus (HPV) infection in women from West India, although incidence of and mortality from cervical cancer is high. METHODS: Cervical specimens were collected, and questionnaires on lifestyle and reproductive factors were administered to 27,192 ever-married women aged 30 to 59 years living in a rural area of Maharashtra State, India. HPV-DNA status for high-risk HPV types was assessed using the second-generation hybrid-capture II assay. RESULTS: The prevalence of HPV infection was 10.3% in this population of middle-aged women. High-risk HPV infection was associated with increasing age, low education level, manual work, early age at first sexual intercourse, and widowhood or separation. CONCLUSION: Low socioeconomic status and vulnerable social groups such as widows and separated women are at a higher risk of HPV infection. This study demonstrates once again that HPV infection and subsequent cervical cancer are social diseases.

HPV screening for cervical cancer in rural India.

BACKGROUND: In October 1999, we began to measure the effect of a single round of screening by testing for human papillomavirus (HPV), cytologic testing, or visual inspection of the cervix with acetic acid (VIA) on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India. METHODS: In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment. RESULTS: In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval [CI], 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women. CONCLUSIONS: In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.

Screening for cervical cancer in India: How much will it cost? A trial based analysis of the cost per case detected.

The cost and cost effectiveness of screening previously unscreened women by VIA, cytology or HPV testing was investigated within a large cluster randomised trial involving 131,178 women in rural India. All resources involved in implementation, training, management, recruitment, screening and diagnosis were identified and costed. We estimated the total costs and detection rates for each cluster and used these data to calculate an average cluster cost and detection rate for each screening approach. These estimates were combined to estimate a cost per case of cervical intraepithelial neoplasia grade 2/3 or invasive cancer (CIN 2/3+) detected. The average total costs per 1,000 women eligible for screening were US dollar 3,917, US dollar 6,609 and US dollar 11,779 with VIA, cytology and HPV respectively. The cost of detecting a case of CIN2/3+ using VIA was dollar 522 (95% CI dollar 429- dollar 652). Our results suggest that more CIN2/3+ cases would be detected in the same population if cytology were used instead of VIA and each additional case would cost US dollar 1065 (95% CI dollar 713- dollar2175). Delivering cervical cancer screening is potentially expensive in a low-income country although costs might be lower outside a trial setting. We found screening with VIA to be the least expensive option, but it also detected fewer cases of CIN2/3+ than other methods; its long-term cost-effectiveness will depend on the long-term benefits of early detection. Cytology was more effective at detecting cases than VIA but was also more expensive. Our findings indicate that HPV may not be a cost effective screening strategy in India at current consumable prices.

A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India.

The impact of screening by visual inspection with acetic acid (VIA), cytology or HPV testing on cervical cancer incidence and mortality is investigated in a cluster randomized controlled trial in India. We report findings after the screening phase, when 52 clusters, with a total of 142,701 women aged 30-59 years in Osmanabad District, India, were randomized into 4 arms for a single round of screening by trained midwives with either VIA, cytology or HPV testing as well as a control group. All laboratory tests were done locally. Test-positive women underwent investigations (colposcopy/biopsy) and treatment in the base hospital. Data on participation, test positivity, positive predictive value and detection rates of cervical neoplasia were analyzed using cluster design methodology. Of the eligible women, 72-74% were screened. Test positivity rates were 14.0% for VIA, 7.0% for cytology and 10.3% for HPV. The detection rate of high-grade lesions was similar in all intervention arms (0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing) (p = 0.06, Mann-Whitney test). While the detection rate for VIA dropped to 0.5% with declining test positivity during the course of the study, it remained constant for cytology and HPV testing. Over 85% of women with high-grade lesions received treatment. Our results show that a high level of participation and good-quality cytology can be achieved in low-resource settings. VIA is a useful alternative but requires careful monitoring. Detection rates obtained by HPV testing were similar to cytology, despite higher investments.

[Cholelithiasis and homozygote drepanocytosis in children in Dakar (Senegal)]. / Lithiase biliaire et drépanocytose homozygote en pédiatrie à Dakar (Sénégal).

BACKGROUND: Cholelithiasis is a well recognized complication of sickle-cell anemia (SCA) because of chronic hemolysis. It is usually asymptomatic but may result in acute cholecystitis or cholangitis. The aim of this study was to assess prevalence of cholelithiasis and its associated factors among Senegalese children and adolescents with SCA. PATIENTS AND METHODS: We analyzed the follow-up records and results of systematic clinical, biological and ultrasonographic examinations in 106 patients with SCA aged 11 months to 22 years (median: 10 years, 6 months), followed up in the Albert-Royer Children's Hospital (Dakar). RESULTS: Cholelithiasis was detected in 9.4% of the patients. Gender, ethnic group, geographic origin and socioeconomic conditions did not have any association with cholelithiasis frequency. The youngest patient with cholelithiasis was 7 years old, and prevalence of cholelithiasis increased with age. The mean age at the beginning of SCA follow-up was higher among patients with cholelithiasis. They were more frequently transfused and tended to present more frequent pain crises and other complications of SCA. We found no spontaneous clinical manifestations attributed to cholelithiasis. Nevertheless, provoked right upper quadrant pain was more frequently observed in patients with cholelithiasis. Fetal hemoglobin, steady-state hemoglobin, reticulocytes count, serum bilirubin, alkaline phosphatase and transaminase levels were not significantly different in these patients, compared to the others. However, those with cholelithiasis had significantly higher mean red cell volume. CONCLUSION: Prevalence of cholelithiasis appears relatively low in Senegalese patients with SCA, probably owing to the tolerance of the Senegal haplotype. Advanced age and severe chronic hemolysis are etiologic factors in evidence. We recommend systematic abdominal ultrasound at least once a year for patients older than 5 years, or when right upper quadrant pain is observed. Cholecystectomy should be performed in cases of cholelithiasis in order to prevent complications.

[Spontaneous pneumothorax disclosing isolated pleural involvement caused by Pneumocystis carinii in an AIDS patient]. / Pneumothorax spontané révélant une atteinte pleurale isolée à Pneumocystis carinii chez un patient atteint de SIDA.

We report a case of apparently isolated pleural Pneumocystis carinii infection in an AIDS patient under primary prophylaxis with pentamidine aerosols. Owing to the absence of the usual radiological signs and to negative broncho-alveolar lavages the diagnosis was difficult, and only pleural biopsy during thoracotomy made it possible. P. carinii cysts were demonstrated by Grocott's silver staining. Histological study of lung biopsy fragments only showed giant-cell granulomas of the foreign body type, with numerous calcifications. The occurrence of pneumothorax, ascribable in this patient to a minute and probably missed pulmonary focal lesion, was caused by the rupture of bullae remaining from an old tuberculosis.