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Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts.To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses.Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314).Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months.The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers.Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart.Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes.clinicaltrials.gov Identifier: NCT01984697.

To present a combined analysis of the pregnancy outcomes for women aged up to 45 years enrolled in five phase III clinical studies of the prophylactic quadrivalent human papillomavirus 6/11/16/18 vaccine.Twenty thousand five hundred fifty-one women aged 15-45 years received quadrivalent HPV vaccine or placebo at day 1 and months 2 and 6. Urine pregnancy tests were performed immediately before each injection; participants testing positive were not vaccinated. Women who became pregnant after enrollment were discontinued from further vaccination until resolution of pregnancy. All pregnancies were followed for outcomes.During the studies, 1,796 vaccine and 1,824 placebo recipients became pregnant, resulting in 2,008 and 2,029 pregnancies with known outcomes. No significant differences were noted overall for the proportions of pregnancies resulting in live birth, fetal loss, or spontaneous abortion. A total of 40 neonates born to vaccinated women and 30 neonates born to women given placebo had one or more congenital anomalies (P=.20). The anomalies were diverse and consistent with those most commonly observed in the general population. The vaccine was well tolerated among women who became pregnant.Administration of quadrivalent human papillomavirus vaccine to women who became pregnant during the phase III clinical trials did not appear to negatively affect pregnancy outcomes. The vaccine is a U.S. Food and Drug Administration pregnancy category B medication (animal studies revealed no evidence of fetal harm, but there are no adequate and well-controlled studies in pregnant women); however, vaccination is not recommended during pregnancy. Postlicensure surveillance is ongoing.ClinicalTrials.gov, www.clinicaltrials.gov, NCT00092521, NCT00092534, NCT00092495, NCT00092547 and NCT00090220.II.

BACKGROUND: A prophylactic quadrivalent human papillomavirus (HPV) vaccine could benefit adult women if they are susceptible to incident genital HPV infections and are acquiring new infections with vaccine HPV types to which they were previously not exposed. This report presents baseline and prospective data from a randomized double-blind placebo-controlled trial of the safety immunogenicity and efficacy of the quadrivalent HPV (Type 6/11/16/18) vaccine in women ages 24 to 45. METHODS: We present the results of an epidemiologic analysis of 3730 women enrolled in a quadrivalent HPV vaccine efficacy trial between June 18 2004 and April 30 2008. Subjects were enrolled from 7 countries (Colombia France Germany Philippines Spain Thailand and the United States) through community and academic health centers and primary health care providers. RESULTS: Average baseline prevalence of anogenital infection and/or seropositivity was 32.8% for >or=1 vaccine HPV types and 0.3% for all vaccine HPV types. Incidence of anogential infection with any vaccine HPV type was approximately 10.5%. The rate of persistent infection was approximately 5% over a 30-month period among women in the placebo arm naive to the relevant type at baseline. Predictors of incident infection included younger age marital status other than first marriage higher number of lifetime and recent sex partners and Chlamydia/gonorrhea infection at baseline. CONCLUSIONS: These findings indicate that women up to age 45 are susceptible to vaccine HPV types and some are acquiring anogenital infections with vaccine HPV types. Future study concerning incident and prevalent HPV infection among women up to age 45 is warranted (Trial NCT number NCT00090220).

BACKGROUND Host genetic factors, such as HLA alleles, play an important role in mediating the course of HIV-1 disease progression through largely undefined mechanisms. OBJECTIVES To examine the association of HLA markers with HIV-1 RNA plasma viral load and other factors associated with course of disease progression in HIV-1 infection. DESIGN AND METHODS A group of 139 HIV-1 seroconverters from the Multicenter AIDS Cohort Study had been typed for a variety of HLA markers. HIV-1 RNA plasma viral load was measured from frozen plasma specimens obtained approximately 9 months following seroconversion. CD4+ cell counts were available from the same study visit. Statistical analysis was performed using survival techniques and linear regression models to quantify the relative associations of an HLA score profile, HIV-1 RNA plasma viral load, CD4+ cell count and age with each other and with rate of progression to AIDS and death. RESULTS Cox proportional hazards models showed statistically significant differences in time to AIDS by HLA score profile category per unit increase [relative hazard (RH), 0.64; P < 0.0001], HIV-1 RNA plasma viral load per 10-fold increase (RH, 2.04; P = 0.0003), and CD4+ cell count per 100 cell (x 10(6)/l) increase (RH, 0.90; P = 0.02). Multivariate linear regression showed that viral load was 39% lower (P = 0.0001) for each unit increase in HLA score profile and 13% lower (P = 0.002) for each 100 cell (x 10(6)/l) increase in CD4+ cell count. CONCLUSION The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV-1 RNA plasma viral load during the first 6-12 months following acute infection.

Objective: To determine the effect of sun exposure on HIV progression. Design: Cross-sectional survey nested within a longitudinal cohort study. Setting: The Multicenter AIDS Cohort Study. Participants: A total of 1155 white HIV-seronegative and 496 white HIV-seropositive homosexual men, of whom 142 serconverted during the study. Main outcome measures: T-helper lymphocyte decline and AIDS. Results: No positive correlation was found between the development of AIDS or loss of T-helper lymphocytes and (i) phenotypic characteristics associated with enhanced ultraviolet radiation (UVR) sensitivity (hair or eye color, skin type), or (ii) reported UVR exposure (sun lamp/tanning bed use, frequency of beach vacations, sunscreen use), or (iii) composite score of UVR sensitivity and exposure history. The composite scores and individual measures of risk were not correlated with rate of T-helper lymphocyte decline (slope based upon rank correlation (correlation coefficient, 0.04; P = 0.32). In fact, individuals purposefully seeking the sun had slower T-helper lymphocyte declines. Sensitivity to UVR was also not significantly associated with AIDS odds ratio (OR), 1.11 per unit of higher composite score; 95% confidence interval (CI), 0.66-1.88; P = 0.63]. Among individuals who were HIV-infected at baseline, those who have been purposely seeking sun exposure were less likely to have AIDS (OR, 0.67; 9.5% CI, 0.39-1.11 ; P = 0.12). Conclusions: These data suggest that phenotypic characteristics of high UVR sensitivity and exposure are not highly correlated with decline in T-helper lymphocyte count or with progression to AIDS.

Objective: To examine the associations between serum vitamin A and E levels and risk of progression to three key outcomes in HIV-1 infection: first AIDS diagnosis, CD4+ cell decline to < 200 cells x 10 6 /l, and mortality. Design: Non-concurrent prospective study. Methods: Serum levels of vitamins A and E were measured at the enrollment visit of 311 HIV-seroprevalent homo-/bisexual men participating in the Baltimore/ Washington DC site of the Multicenter AIDS Cohort Study. Cox proportional hazards models were used to estimate the relative hazard of progression to each outcome over the subsequent 9 years, adjusting for several independent covariates. Results: Men in the highest quartile of serum vitamin E levels (≥ 23.5 μmol/l) showed a 34% decrease in risk of progression to AIDS compared with those in the lowest quartile Irelative hazard (RH), 0.66; 95% confidence interval (CI), 0.41-1.06)1. This effect was statistically significant when comparing the highest quartile of serum vitamin E to the remainder of the cohort (RH, 0.67; 95%, CI, 0.45-0.98). Associations between serum vitamin A levels and risk of progression to AIDS were less clear, but vitamin A levels were uniformly in the normal to high range (median = 2.44 μmol/l). Similar trends were observed for each vitamin with mortality as the outcome, but neither vitamin was associated with CD4+ cell decline to < 200 cells x 10 6 /l. Men who reported current use of multivitamin or single vitamin E supplements had significantly higher serum tocopherol levels than those who were not taking supplements (P = 0.0001). Serum retinol levels were unrelated to intake of multivitamin or single vitamin A supplements. Conclusions: These data suggest that high serum levels of vitamin E may be associated with slower HIV-1 disease progression, but no relationship was observed between retinol levels and disease progression in this vitamin A-replete population.

The association between early virologic and immunologic events after human immunodeficiency virus type 1 (HIV-1) infection and progression of HIV-1 infection to acquired immunodeficiency syndrome (AIDS) was studied among 59 homosexual men with documented time of seroconversion. Epidemiologic factors, such as number of lifetime sexual partners, history of sexually transmitted diseases, and other factors, also were studied. All 17 seroconverters in the cohort who developed AIDS within 3 years (rapid progressors = RPs) were compared with 42 men without AIDS for at least 6 years seroconversion (nonrapid progressors = non-RPs). Plasma levels of HIV-1 RNA, p24 antigen, antibodies to HIV-1 structural genes, beta-2 microglobulin, neopterin, and interferon-alpha were measured at four time points: (a) the last seronegative visit, (b) the first seropositive visit, (c) the visit closest to AIDS (or the corresponding visit for the non-RPs) and (d) 6 years after seroconversion (for non-RPs). Up to seroconversion, the RPs had a significantly higher number of lifetime sexual partners than non-RPs (503 versus 171, respectively). At the first seropositive visit, RPs had significantly higher concentrations of plasma HIV-1 RNA (p < 0.01) and prevalence of p24 antigenemia (p < 0.001) and significantly lower levels of antibodies to the HIV-1 gag proteins p17 and p24 (p < 0.01-0.001) compared with non-RPs. These differences increased during follow-up visits. Antibodies to p66 and gp120 were significantly different only at the visit closet to AIDS (p < 0.001), as were beta-2 microglobulin and interferon alpha. These findings suggest that early virologic-immunologic events after HIV-1 infection may determine the rate of progression to AIDS. Anti-gag immune response may prevent rapid progression of HIV-1 disease and should be considered for future vaccine studies.

The authors evaluated the diagnostic utility and prognostic value of immune-complex-dissociated (ICD) HIV-1 p24 antigen detection in a prospective cohort study of perinatally acquired HIV-1 infection in Butare Rwanda. HIV-1 p24 antigen was measured after acid dissociation in plasma samples collected at 6 weeks and 3 months of age from 36 HIV-1 infected and 80 uninfected children born to HIV-1 infected women. Among children with persistent HIV-1 antibody after 12 months of age 26.7% of samples tested ICD HIV-1 p24 antigen positive. Among children who died between 3 and 12 months of age but were classified as HIV-1 infected 17.6% tested p24 antigen positive at 6 weeks of age and 33.3% at 3 months of age. Female infants were more likely to test p24 antigen positive than male infants (p = 0.046). The specificity of the assay was 96.8%. Cumulative probabilities of child survival to 36 months of age were computed by HIV-1 status of the child and early p24 antigenemia. The mean survival time was 7 months for HIV-1 infected children with a high (> 50 pg/ml) p24 antigen concentration vs 20 months for children with p24 antigen concentrations between 10 and 50 pg/ml (p = 0.02). Cumulative probabilities of survival to 36 months of age were 0% among HIV-1 infected children with at least one positive p24 antigen test 44% among confirmed HIV-1 infected children who were p24 antigen-negative at both 6 weeks and 3 months of age and 95% among seroconverting children (p < 0.001). These results suggest a lower sensitivity of the ICD HIV-1 p24 antigen assay among Rwandan children compared with previous reports from developed countries. However a positive p24 antigen test was strongly predictive of rapid progression to AIDS and early death. (authors)

To investigate the risk of occupationally acquired HIV infection among traditional birth attendants (TBA) in Rwanda, Africa.A serosurvey was conducted among 219 TBA practicing in a rural but densely populated area in southern Rwanda. Each TBA was interviewed about sociodemographic information, work-related habits and practices, and presence of nonoccupational risk factors for HIV infection. The frequency of skin exposure to HIV-infected blood was estimated for each TBA from HIV seroprevalence data collected previously from pregnant women stratified by the geographic zones in which the TBA practiced.Four TBA (1.8%) tested HIV-1-antibody-positive; all four had reported nonoccupational risk factors for HIV infection. We estimated that the 215 HIV-negative TBA had 2234 potentially infectious blood-skin contacts out of a total of approximately 35,000 deliveries assisted in the past 5 years. However, we found no evidence of HIV infection caused by occupational blood contact (none out of 2234; upper limit of the 95% confidence interval because of one potentially infectious blood-skin contact = 0.2%).Although these findings may not be universal to all TBA in Africa, the risk of occupationally acquired HIV infection among TBA appears small. The high frequency of blood-skin contact among TBA in Rwanda highlights the need to include infection control precautions in the training of TBA.Samples of blood from 219 traditional birth attendants (TBA) practicing in a rural, densely populated area in southern Rwanda were tested for the presence of antibody against HIV-1 in an investigation of the risk for acquiring HIV infection occupationally. The TBAs were interviewed for sociodemographic data, on work-related habits and practices, and about nonoccupational risk factors for HIV infection. The researchers also estimated the frequency of skin exposure to HIV-infected blood for each TBA from HIV seroprevalence data collected previously from pregnant women stratified by the geographic zones in which each TBA practiced. Four TBAs tested seropositive for HIV-1 antibody; all had reported nonoccupational risk factors for infection. It was also estimated that the 215 HIV-negative TBAs had 2234 potentially infectious blood-skin contacts out of a total of approximately 35,000 deliveries assisted over the previous past five years. No evidence was therefore found of HIV infection caused by occupational blood contact and the risk of occupationally acquired HIV infection among TBAs seems small. The high frequency of blood-skin contact among TBAs in Rwanda, however, highlights the need to include infection control precautions in the training of TBAs.

A prospective cohort study of 318 human immunodeficiency virus 1 (HIV-1)-infected and 309 seronegative pregnant women was carried out in Butare, Rwanda. Birth weight was significantly lower among singleton infants born alive to HIV-1-infected mothers compared with those born alive to seronegative mothers (2706 g vs. 2825 g; P = 0.002). Crown-to-heel length, head circumference, chest circumference and placental weight were also reduced. Maternal HIV-1 infection was significantly associated with intrauterine growth retardation but not with preterm birth. Differences in the body mass index and weight/head ratio suggest that the adverse impact on live born infants may have been most severe towards the end of pregnancy, resulting in a lean infant with a relatively large head. The higher frequency of intrauterine growth retardation could not be explained by potential confounding factors such as maternal cigarette smoking, history of sexually transmitted diseases or sociodemographic characteristics. The neonatal physical examination did not reveal any differences in clinical signs or symptoms within 48 hours of birth except for the presence of conjunctivitis which was more common among infants of HIV-1-infected mothers. The perinatal and neonatal mortality rates were not significantly affected by maternal HIV-1 status.

Reiter's syndrome has been reported to occur in up to 10% of patients with HIV infection. However, no properly controlled epidemiological studies have been conducted to determine whether HIV infection is an independent risk factor or whether the immunodeficiency induced by HIV infection is permissive for infection with other arthritogenic organisms. The prevalence and incidence of Reiter's syndrome were determined in 1133 homosexual/bisexual men enrolled in the Johns Hopkins Multicenter AIDS Cohort Study. There was no difference in the prevalence of Reiter's syndrome at entry into the study in 1984 between 357 HIV-positive and 776 HIV-negative men: five per 1000 in both groups. During 5 years' follow-up, one case of Reiter's syndrome developed among each group of HIV-positive and HIV-negative men. These data fail to support a direct etiological role for HIV infection in the development of Reiter's syndrome.

Prospective follow-up of 172 HIV-infected pregnant women and their infants was conducted at Mulago Hospital, Kampala, Uganda during 1990 to 1992. Information was collected on maternal immune status (CD4 counts or clinical AIDS), and concurrent infections with sexually transmitted diseases. Infants were observed on a follow-up basis to determine HIV infection, using polymerase chain reaction (PCR) under 15 months of age and enzyme immunoassay/Western blot for those older than 15 months. Placental membrane inflammation (chorioamnionitis and funisitis), and placental villous inflammation (villitis, intervillitis, and deciduitis) were diagnosed by histopathology. Mother-to-child HIV transmission rates were assessed, and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) of transmission were estimated using women with no placental pathology or evidence of immune suppression as a reference group.The overall mother-to-child HIV transmission rate was 23.3%. Women with no placental membrane inflammation or immune suppression had a transmission rate of 11.3%; compared with 25.5% in women with placental inflammation and no immunosuppression (adjusted OR, 2.87; 95% CI, 1.04-7.90), and 37.0% in immunosuppressed women (OR, 3.07; 95% CI, 1.42-6.67). We estimate that 34% of HIV transmission could be prevented by treatment of placental membrane inflammation in nonimmunocompromised women. Transmission rates were 40.9% with genital ulcer disease (OR, 3.57; 95% CI, 1.28-9.66). Placental villous inflammation and artificial rupture of membranes did not increase transmission rates and cesarean section was associated with a nonsignificant reduction of risk (OR, 0.70; 95% CI 0.24-2.06).Placental membrane inflammation increases the rate of mother-to-child HIV transmission.

Two rough methods are given to estimate the combined HIV prevalence in Los Angeles, New York and San Francisco in homosexual men. Both methods are related to the back calculation technique, and use AIDS surveillance data and information obtained from the Multicenter AIDS Cohort Study. Both methods suggest that the combined HIV prevalence is approximately 100,000, with a possible range of 80,000-140,000.