Emergence of HIV-1 drug-resistant variants in women following antiretroviral prophylaxis for the prevention of mother to child transmission.

PURPOSE: Emergence of drug resistance following HIV prophylaxis has an important impact on ART program. OBJECTIVE: To investigate the emergence of drug resistance in HIV-1 infected pregnant women. MATERIALS AND METHODS: Fifty-three HIV-1 infected pregnant women who had received 4-12 weeks of antenatal AZT followed by Nevirapine during delivery and Combivir [AZT + 3TC] for 1 week postpartum (group-1, n = 48) or who come at the time of delivery and received Nevirapine followed by Combivir for 1 week (group-2, n = 5) were recruited. Samples were collected prior to the start of the prophylaxis and 5-8 weeks postpartum. In addition, a third sample was collected between 26-65 weeks postpartum from 7 women. Amplification of HIV-1 pol gene and drug resistance analysis was done. RESULT: Two (3.8%) women in group-1 showed transmitted drug resistance and they continued to show this even at 6 weeks postpartum. One (2%) woman from group-1 showed a mutation after 6-8 weeks of prophylaxis. Among the samples collected between 26-65 weeks postpartum, 3/7 (43%) showed mutations and all these women belong to group-1. Women belonging to group-2 didn't show mutation prior to or following prophylaxis. CONCLUSION: In contrast to the available data among pregnant women with ART prophylaxis, our data showed reduced frequency of mutations following 5-8 weeks of postpartum but an emergence of mutation later (26-65 weeks). The addition of Combivir with the single dose Nevirapine during delivery and the early stage of the disease with higher CD4 counts could be the reasons for this.

Molecular variants of HPV-16 associated with cervical cancer in Indian population.

Human papilloma virus is a causative factor in the etiology of cervical cancer with HPV16 being the most prevalent genotype associated with it. Intratype variations in oncogenic E6/E7 and capsid L1 proteins of HPV 16 besides being of phylogenetic importance, are associated with risk of viral persistence and progression. The objective of this multicentric study was to identify HPV-16 E6, E7 and L1 variants prevalent in India and their possible biological effects. Squamous cell cervical cancer biopsies were collected from 6 centres in India and examined for the presence of HPV 16. Variants of HPV-16 were characterized by full length sequence analysis of L1, E6 and E7 genes in 412 samples. Similar distribution of the variants was seen from the different centres/regions, with the European variant E350G being the most prevalent (58%), followed by American Asian variant (11.4%). Fifty six changes were seen in E6 region, 31 being nonsynonymous. The most frequent being L83V (72.3%), Q14H (13.1%) and H78Y (12.1%). Twenty-nine alterations were seen in E7 region, with 12 being nonsynonymous. The most frequent being F57V (9%). L1 region showed 204 changes, of which 67 were nonsynonymous. The most frequent being 448insS (100%), and 465delD (100%), H228D (94%), T292A (85%). The identified variants some new and some already reported can disrupt pentamer formation, transcriptional regulation of the virus, L1 protein interface interaction, B and T cell epitopes, p53 degradation, and thus their distribution is important for development of HPV diagnostics, vaccine, and for therapeutic purpose.

An overview of human papillomaviruses and current vaccine strategies.

Cervical cancer is one of the most common cancers in women worldwide, particularly in developing countries. The viral origin of cervical cancer has been proven beyond any reasonable doubt. Persistent infection with certain subsets of human papillomaviruses is recognized as a necessary cause for the development of cervical cancer. Persistence of oncogenic HPVs, immunodeficiency, high HPV viral load and cofactors like smoking, multiple sex partners and poor nutrition predispose to cervical cancer. Prophylactic vaccines using HPV virus-like particles containing capsid protein L1 have shown protection against disease in animals and are currently undergoing clinical trials. Therapeutic vaccines using HPV E6 and E7 proteins are also being investigated for their ability to remove residual infection.

Human papillomavirus genotypes associated with cervical neoplasia in India.

The aim of this study was to determine the prevalence of human papillomavirus (HPV) genotypes in tissue with cervical neoplasias in patients from south and east India. Cross-sectional cervical tissue was obtained from 100 patients from south India and 30 patients from east India who had a biopsy for clinically invasive cervical cancer or cervical intraepithelial neoplasia (CIN) in a tertiary care hospital in India. DNA amplification was done with biotinylated PGMY 09/11 primers, and the line blot assay was used to determine the HPV genotype. HPV DNA was detected in 95% of invasive cancers (113/119) and 91% of CINs (10/11). A single HPV type was found in 100 women (77%), and mixed infections were found in 23 women (18%). HPV 16 (60%) and HPV 18 (14%) were the most frequent types, but 16 other types (26, 31, 33, 35, 42, 45, 51, 52, 53, 56, 58, 61, 62, 64, 81, and 82) were also identified. HPV 16 was present in 63% of patients from south India and in 50% of patients from east India, while HPV 18 was present in 12% and 20%, respectively. There are several high-risk HPV types associated with cervical neoplasias of which types 16 and 18 are the most common.

Community prevalence of hepatitis B infection and modes of transmission in Tamil Nadu, India.

BACKGROUND AND OBJECTIVE: There have been very few community based studies on prevalence of hepatitis B virus (HBV) infection in India. We undertook this study to determine the prevalence of HBV infection in a southern State of India, Tamil Nadu and to describe the important factors related to transmission of the virus in the community. METHODS: Analysis of stored blood samples from a representative population of Tamil Nadu from an earlier community cluster survey on sexually transmitted diseases (STD) prevalence using proportionate to population size (PPS) technique was done. Serum markers of HBV viz., hapatitis B surface antigen (HBsAg), hepatitis B e antigen (HBe Ag) and antibody to surface antigen (anti-HBs) were performed. RESULTS: 1981 subjects were screened in the study. HBsAg prevalence was 5.7 per cent (CI 4.6- 6.8) with 23.5 per cent (25/106) of these having positive HBe-antigen. Community seroprevalence (HbsAg + anti-HBs) of hepatitis B infection was 27.4 per cent (CI: 25.3-29.5) with the highest prevalence of 32.7 per cent (CI: 30.2-35.2) noted in the 15-20 yr age group. Significant independent association (OR 1.4; P=0.006) was detected with family history of exposure to HBV infection by logistic modeling. Other risk factors noted to have significant association were use of disposable needles during injection (OR 0.5; P=0.02) in men, smoking (OR 3; P=0.04) and use of condom (OR 0.6; P=0.08) in women. INTERPRETATION AND CONCLUSION: This community based study shows a high prevalence of hepatitis B infection in the state of Tamil Nadu with the highest prevalence being in the younger (15-20 yr) age group. High prevalence rate in childhood with e-antigenemia seen in 23.5 per cent of HBsAg positive subjects suggest childhood transmission. Poor injection practices and high-risk sexual behavior were found to be additional risk factors for transmission of the disease in the community.

Genital syndromes and syndromic management of vaginal discharge in a community setting.

The objective of the study was to determine the community prevalence of genital syndromes in women and evaluate the syndromic management of vaginal discharge in this setting. A representative sample for the state of Tamilnadu was chosen using probability proportional to size cluster technique. Thirty clusters were selected from three districts. Demographic, sexual behaviour, risk factors, clinical and laboratory data were collected from the selected population using a structured questionnaire. Direct smear examination for Trichomonas vaginalis, culture for Neisseria gonorrhoeae and Haemophilus ducreyi, serological tests for syphilis (RPR and TPHA), hepatitis B (Hbs Ag ELISA), IgM and IgG antibodies to HSV2 (Novum diagnostics, Germany) and PCR test for detection of C. trachomatis from urine were done. There were 1157 women in the selected population. On examination, vaginal discharge was the most common genital syndrome (38.4%). The sensitivity, specificity, positive and negative predictive value of vaginal discharge as a marker for STD in women was found to be 43.3%, 61.6%, 10.7% and 91.1%, respectively. We concluded that treatment on the basis of syndromic management would result in over-treatment of 90% of women with vaginal discharge.

Birthweight-specific neonatal mortality in developing countries and obstetric practices.

OBJECTIVES: To evaluate birthweight-specific neonatal mortality and perinatal interventions in major medical centers in developed and developing countries. METHODS: A survey was developed and electronically mailed to 13 medical centers participating in the Global Network for Perinatal and Reproductive Health (GNPRH). The ability of a center to provide requested data was assessed. The mortality rates and use of specific perinatal interventions in centers in developing countries were compared with developed countries. RESULTS: Nine centers in developing countries responded to the survey, and three centers in developed countries were used for comparison. Data collection was highly variable. Most developing country centers were able to provide data by birthweight but not by gestational age. The differences in mortality rates between developing and developed countries were more pronounced at lower gestational ages and birthweights. A difference was found in perinatal interventions between developing and developed countries. In the former, viability was generally considered 28 weeks, and the gestational age at which cesarean sections were usually performed for the sake of the fetus at preterm gestations varied from 26 to 37 weeks. Most centers did not routinely induce for pPROM; only five out of nine centers used antibiotics to prolong latency. Most centers used tocolysis beginning at 26-28 weeks through 32-37 weeks, and a variety of tocolytic agents were used. Most centers routinely used corticosteroids for preterm infants, and all centers employed repeat weekly steroid dosing if undelivered. CONCLUSIONS: Despite the fact that the GNPRH centers included in this study represent some of the best health care available in these countries, they lag far behind centers in developed countries in neonatal mortality rates and their use of various obstetric practices. Furthermore, incomplete and inconsistent data collection complicates the evaluation of the factors contributing to high neonatal mortality rates.

An international survey of practice variation in the use of antibiotic prophylaxis in cesarean section.

OBJECTIVE: To examine the use of antibiotic prophylaxis in cesarean section in different countries and in relation to a reference regimen. METHOD: Fifty consecutive cesarean sections performed in eight centers in five countries were surveyed. Data from each center were compared to a regimen recommended by the Cochrane Collaboration (one dose of ampicillin or cefazolin administered to all women shortly before the procedure or immediately after cord clamping) using logistic regression with adjustment for procedure type. RESULT: Prophylaxis was used widely, but only four centers administered prophylaxis to all women. Ampicillin and cefazolin were the principal antibiotics used, but broad-spectrum agents and multidrug regimens were also used commonly. Only two centers reliably administered the antibiotic at the appropriate time. The majority of women received only one dose of antibiotic in only three centers. CONCLUSION: The use of antibiotic prophylaxis in cesarean section was variable and often at odds with published recommendations.

Hyperfractionation in carcinoma of the cervix: tumor control and late bowel complications.

PURPOSE: Hyperfractionation has been advocated to improve local tumor control by increasing radiation dose without increasing late normal tissue complications. The aim of this study was to determine if hyperfractionation decreased late bowel complications. METHODS AND MATERIALS: Thirty patients with Stage II and III cervical cancer were randomized to receive either hyperfractionation or conventional fractionation. Patients were followed for 5 years and monitored for tumor control, recurrence, and bowel complications. The relative risks of tumor control and bowel complications were computed at 1 year and 5 years of follow-up. Kaplan-Meier survival curves were plotted to determine probabilities of being tumor-free and bowel complication-free. RESULTS: There were 15 patients in each group. At 1 year of follow-up, 2 patients in the hyperfractionation group (13%) and 7 patients in the conventional treatment group (45%) had tumor (relative risk [RR] 0.3; 95% confidence interval [CI] 0.1, 1.1; p = 0.054). Delayed bowel complications were seen in 8 patients in the hyperfractionation group and 1 patient in the conventional treatment group (RR 7.5; 95% CI 1.1, 52; p = 0.014). At 5 years, 2 patients in the hyperfractionation group and 8 patients in the conventional treatment group had tumor (RR 0.3; 95% CI 0.1, 1.1; p = 0.04). Delayed bowel complications (Grades 2 and 3) occurred in 9 women in the hyperfractionation group and 2 patients in the conventional group (RR 5.4; 95% CI 1.5, 19.5; p = 0.0006). Kaplan-Meier analysis showed that the hyperfractionation group had significantly more bowel complications over the 5 years of follow-up (p = 0.024). CONCLUSION: Hyperfractionation may result in better tumor control both at 1 year and at 5 years following treatment of cervical cancer. However, hyperfractionation could lead to increased late bowel complications and must be used judiciously in the treatment of cervical cancer.

Effect of hypertensive diseases in pregnancy on birthweight, gestational duration, and small-for-gestational-age births.

We measured the impact of hypertensive disorders in pregnancy (chronic hypertension, pregnancy-induced hypertension, and eclampsia) on birthweight, gestational duration, and small-for-gestational-age births. We employed a retrospective cohort design using North Carolina birth certificate data for the years 1988-1990, with the analyses based on nearly 300,000 pregnancies. Women noted to have eclampsia during pregnancy had a substantially greater risk of delivering very-low-birthweight infants (birthweight < or = 1,499 gm; risk difference (RD) = 6.7%) and moderately-low-birthweight infants (1,500-2,499 gm; RD = 14.6%), and very preterm (gestational age < 33 weeks; RD = 7.1%) and moderately preterm (33-36 weeks; RD = 9.3%) births, compared with women without hypertension. Corresponding risk differences for these outcomes were 1.9% and 5.1% for very low and moderately low birthweight, and 1.6% and 3.0% for very preterm and moderately preterm for women with chronic hypertension. Risk differences were of similar magnitude for women with pregnancy-induced hypertension for these outcomes. Hypertensive disorders in pregnancy were associated with small-for-gestational-age infants, with risk differences of 5.1%, 3.5%, and 9.2% for chronic hypertension, pregnancy-induced hypertension, and eclampsia, respectively. The patterns of risk were similar for preterm births due to spontaneous onset of labor and those due to other precipitating events. We observed similar patterns for black and white women. Control for confounders through multivariable logistic regression models did not alter the observed patterns. In spite of the limited data quality, we found that hypertensive disorders in pregnancy substantially increase the risk of low birthweight, preterm births, and small-for-gestational-age births.

The normal preterm foetal heart rate pattern.

A longitudinal study was carried out on 38 women with low risk pregnancies. These women had cardiotocography at 27-28 wk initially, at fortnightly intervals thereafter until 36 wk and at weekly intervals thereafter until delivery. All cardiotocographs were analyzed by one investigator who was not aware of the individual clinical situation. Of the 232 cardiotocographs, 12 (0.5%) of poor quality were excluded from analyses. The mean base-line heart rate decreased from 142.5 (SD 6.03) beats per min at 27-30 wk to 138.2 (SD 7.4) at term. Analysis of variance for repeated measures showed that the decrease in foetal heart rate with gestation was statistically significant (P < 0.001). The number of accelerations increased with gestation (P = 0.002). There were no significant changes in variability and decelerations with increasing gestation.

Growth pattern of the Indian fetus.

OBJECTIVES: To determine the pattern of intrauterine growth and the gestation at birth of Indian fetuses. METHOD: One hundred twenty consecutive women who had reliable menstrual histories, low-risk pregnancies and who were booked for delivery at the Christian Medical College Hospital, Vellore, before 20 weeks' gestation were recruited to the study. Ultrasound fetal biometry was carried out at 4-weekly intervals from 20 weeks and at weekly intervals after 36 weeks until delivery. RESULTS: Growth patterns of fetal biparietal diameter and femur length were comparable to those reported in Western populations. However there was a lag in growth of abdominal circumference (AC) after 28 weeks in comparison with that reported in Western populations. The median gestation at delivery following spontaneous labor was 39 weeks. No association was observed between rate of growth of AC and gestation at birth. CONCLUSION: Slowing of growth of the fetal AC after 28 weeks and a shorter length of gestation result in the birth of smaller babies in this ethnic group. The implications of these findings are discussed.

Use of the Foley catheter as a cervical ripening agent prior to induction of labor.

OBJECTIVE: To study the effect of the extraamniotic Foley catheter as a cervical ripening agent prior to induction of labor. METHOD: A descriptive study was carried out on 187 patients who had labor induced following cervical ripening with the extraamniotic Foley catheter. There were 99 nulliparas and 88 multiparas whose labor outcomes were analyzed separately. RESULTS: The mean change in the modified Bishop score was 3.7 for nulliparas and 3.3 for multiparas. The induction-delivery interval was 8.7 h for nulliparas and 5.5 h for multiparas. CONCLUSION: The Foley catheter was found to be an effective agent for cervical ripening in both primiparas and multiparas and its use was not associated with any complications.

Inter- and intra-observer variation in the amniotic fluid index.

OBJECTIVE: To measure inter- and intra-observer reliability in the amniotic fluid index (AFI). METHODS: To measure inter-observer reliability, three observers measured the AFI at random in 32 patients without knowing each other's results. To determine intra-observer reliability, each investigator made repeated measurements on ten other patients. Patients at 26-41 weeks' gestation who were referred for an antenatal ultrasound examination were asked to participate. Intra-observer reliability and inter-observer reliability were expressed as intra-class correlation coefficients. Inter-observer agreement was also expressed as the kappa statistic after dichotomizing the AFI (less than 8 cm, 8 cm or more). RESULTS: The intra-class correlation coefficient for intra-observer reliability exceeded 0.8, and for inter-observer reliability it was 0.67 (95% confidence interval [CI] 0.52-0.79), with an overall kappa of 0.44 (95% CI 0.22-0.65). The percentage disagreement between pairs of observers reached 22-28%. CONCLUSION: Measurements of AFI have good intra-observer and moderate inter-observer agreement. In clinical use, an AFI level near a cutoff value should be interpreted with caution.

Colposcopy in women with a normal Papanicolaou smear.

BACKGROUND: Colposcopy is usually done when the Papanicolaou smear is abnormal so that the necessity for cone biopsy is reduced. However, there is often a strong clinical suspicion of cervical neoplasia even though the smear is normal and this problem of the false negative Papanicolaou smear has not, we feel, been adequately addressed. We, therefore, examined the usefulness of colposcopy in detecting cervical neoplasia in women in whom the Papanicolaou smear was normal. METHODS: A cross-sectional design was used which included 80 patients in whom cervical neoplasia was suspected and who had undergone colposcopy in one gynaecology unit at the Christian Medical College Hospital, Vellore. The Papanicolaou smear result of these patients was then related to their diagnosis on colposcopy. RESULTS: The Papanicolaou smears were normal in 56 patients and abnormal in 24. In the normal Papanicolaou smear group there were 18 women with grade I cervical intra-epithelial neoplasia and 3 with grade II lesions. In the abnormal smear group there were 8 women with grade I cervical intra-epithelial neoplasia, 9 with grade II cervical intra-epithelial neoplasia and 1 had microinvasive carcinoma. Patients with abnormal Papanicolaou smears had a relative risk of 7.8 (95% CI 2.4 to 25.8) of having a lesion more advanced than grade I cervical intra-epithelial neoplasia compared with those in whom cervical neoplasia was only suspected clinically. CONCLUSION: When the clinician suspects cervical neoplasia but the Papanicolaou smear is negative, colposcopy reveals at least grade II cervical intra-epithelial neoplasia in 5% of patients. Such patients, therefore, need to be followed up closely or else have a colposcopy and directed biopsy.