Efficacy of etravirine combined with darunavir or other ritonavir-boosted protease inhibitors in HIV-1-infected patients: an observational study using pooled European cohort data.

OBJECTIVES: This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. etravirine plus an alternative boosted protease inhibitor (other PI group; n = 116) using pooled European cohort data. METHODS: Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland and UK) cohorts provided data (collected in 2007-2012). Stratum-adjusted (for confounding factors) Mantel-Haenszel differences in virological responses (viral load < 50 HIV-1 RNA copies/mL) and odds ratios (ORs) with 95% confidence intervals (CIs) were derived. RESULTS: Baseline characteristics were balanced between groups except for previous use of antiretrovirals (≥ 10: 63% in the DRV group vs. 49% in the other PI group), including previous use of at least three PIs (64% vs. 53%, respectively) and mean number of PI resistance mutations (2.3 vs. 1.9, respectively). Week 24 responses were 73% vs. 75% (observed) and 49% vs. 43% (missing = failure), respectively. Week 48 responses were 75% vs. 73% and 32% vs. 30%, respectively. All 95% CIs around unadjusted and adjusted differences encompassed 0 (difference in responses) or 1 (ORs). While ORs by cohort indicated heterogeneity in response, for pooled data the difference between unadjusted and adjusted for cohort ORs was small. CONCLUSIONS: These data do not indicate a difference in response between the DRV and other PI groups, although caution should be applied given the small size of the other PI group and the lack of randomization. This suggests that the efficacy and virology results from DUET can be extrapolated to a regimen of etravirine with a boosted PI other than darunavir/ritonavir.

Effects of once-daily darunavir/ritonavir versus lopinavir/ritonavir on metabolic parameters in treatment-naive HIV-1-infected patients at week 96: ARTEMIS.

In the ARTEMIS trial, 689 treatment-naïve, HIV-1-infected adults received darunavir/ritonavir (DRV/r) 800/100 mg every day or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose plus fixed-dose tenofovir/emtricitabine. Week 96 metabolic parameters are reported. Adverse events (AEs) classed as metabolism/nutrition disorders were observed in 14% of DRV/r and 22% of LPV/r patients. Lipid-related AEs were reported in fewer DRV/r (8%) than LPV/r (16%) patients. A small increase in glucose and insulin levels was observed at week 96 in both groups. Lipoma was the only lipodystrophy-related AE reported in >1% of patients (DRV/r, n = 1; LPV/r, n = 4) and no grade 3 or 4 lipodystrophy-related AEs were reported. No clinically relevant changes from baseline were seen in anthropometric measurements in either group. Median mid-waist/hip ratio at week 96 was comparable to baseline in both arms. Over 96 weeks, DRV/r had a similar effect on glucose and insulin levels but a more favourable lipid profile than LPV/r in treatment-naïve, HIV-infected patients.

A prospective study of risk factors for herpes simplex virus type 2 acquisition among high-risk HIV-1 seronegative women in Kenya.

OBJECTIVES: Several studies have demonstrated an association between herpes simplex virus type 2 (HSV-2) and HIV-1, but available data on risk factors for HSV-2 acquisition are limited. The objective of this analysis was to determine the incidence and risk factors for HSV-2 acquisition among HIV-1-seronegative female sex workers in Kenya. METHODS: Between February 1993 and December 2006, HIV-1-seronegative women attending a municipal sexually transmitted infection (STI) clinic were invited to enroll in a prospective cohort study. Screening for HIV-1 and STIs were done at monthly follow-up visits. Archived blood samples were tested for HSV-2. RESULTS: Of 1527 HIV-1-seronegative women enrolled, 302 (20%) were HSV-2 seronegative at baseline of whom 297 had at least one follow-up visit. HSV-2 incidence was high (23 cases/100 person-years; 115 cases). In multivariate analysis, HSV-2 was significantly associated with more recent entry into sex work, workplace and higher number of sex partners per week. Condom use was protective, although this was statistically significant only for the intermediate strata (25-75% condom use; HR 0.43; p = 0.05). There were statistical trends for bacterial vaginosis to increase HSV-2 risk (HR 1.56; p = 0.07) and for oral contraceptive use to decrease risk (HR 0.50; p = 0.08). The 23% annual HSV-2 incidence in this study is among the highest reported anywhere in the world. CONCLUSIONS: Women were at increased risk if they had recently entered sex work, had a higher number of sex partners or worked in bars. HSV-2 risk reduction interventions are urgently needed among high-risk African women.

Hormonal contraception and risk of sexually transmitted disease acquisition: results from a prospective study.

OBJECTIVES: To examine the relationship between use of oral contraceptive pills or depot medroxyprogesterone acetate and sexually transmitted disease acquisition. STUDY DESIGN: Prospective cohort included 948 Kenyan prostitutes. Multivariate Andersen-Gill proportional hazards models were constructed, adjusting for sexual behavioral and demographic variables. RESULTS: When compared with women who were using no contraception, users of oral contraceptive pills were at increased risk for acquisition of chlamydia (hazard ratio, 1.8; 95% confidence interval, 1.1-2.9) and vaginal candidiasis (hazard ratio, 1.5; 95% confidence interval, 1.2-1.9) and at decreased risk for bacterial vaginosis (hazard ratio, 0.8; 95% confidence interval, 0.7-1.0). Women using depot medroxyprogesterone acetate had significantly increased risk of chlamydia infection (hazard ratio, 1.6; 95% confidence interval, 1.1-2.4) and significantly decreased risk of bacterial vaginosis (hazard ratio, 0.7; 95% confidence interval, 0.5-0.8), trichomoniasis (hazard ratio, 0.6; 95% confidence interval, 0.4-1.0), and pelvic inflammatory disease (hazard ratio, 0.4; 95% confidence interval, 0.2-0.7). Consistent condom use was associated with significantly decreased risk of gonorrhea, chlamydia, genital ulcer disease, bacterial vaginosis, and pelvic inflammatory disease. CONCLUSIONS: The use of oral or injectable hormonal contraception altered susceptibility to sexually transmitted diseases, which may in turn influence transmission of human immunodeficiency virus type 1. Consistent condom use was protective with regards to sexually transmitted disease and should be encouraged for the prevention of sexually transmitted disease and human immunodeficiency virus type 1 among women who use hormonal contraception.

Evaluation of a low-dose nonoxynol-9 gel for the prevention of sexually transmitted diseases: a randomized clinical trial.

BACKGROUND: Low-dose nonoxynol-9 products have a potential advantage of reduced toxicity. However, little is known about their efficacy in reducing the incidence of sexually transmitted diseases (STDs). GOAL: To determine the effect that an intravaginal gel containing 52.5 mg of nonoxynol-9 has on the acquisition of STDs in a cohort of HIV-1-seronegative female sex workers in Mombasa, Kenya. STUDY DESIGN: A randomized double-blind placebo controlled trial was performed. RESULTS: In this study, 139 women were randomized to the nonoxynol-9 group and 139 to the placebo group. No significant differences were found between the two study groups in terms of safety outcomes and reported symptoms, except for a lower incidence of vaginal erythema in the nonoxynol-9 group. There was a significantly higher incidence of gonorrhea in the nonoxynol-9 group than in the placebo group. No significant differences were observed between the groups for acquisition of Candida, trichomonas, bacterial vaginosis, C trachomatis, syphilis, or HIV-1, although the statistical power to detect differences for some of these STDs was limited. CONCLUSIONS: In this randomized placebo-controlled trial of a low-dose nonoxynol-9 gel, a significantly higher incidence of gonorrhea was found in the nonoxynol-9 group, but no significant differences between the groups were found for Candida, trichomonas, bacterial vaginosis, C trachomatis, syphilis, or HIV-1.

Impact of an alarm device on medication compliance in women in Mombasa, Kenya.

A randomized controlled clinical trial was conducted to determine the efficacy and acceptability of an alarm device for improving medication compliance among women in resource poor countries. Study participants were given a one-month supply of daily multi-vitamins in an electronic medication vial. Women randomly received either an alarmed vial or a non-alarmed vial. Sixty per cent of women had good compliance (defined as 95% > or = of pills ingested). Women randomized to use the alarmed vial were significantly more likely to have good compliance than those in the non-alarmed control group (82% vs. 36%, P < 0.001). Vial acceptability was high and 99% of participants said they would choose to use the vial again. In conclusion, the alarm device was found to significantly improve medication adherence rates and may be particularly beneficial for improving adherence to antiretroviral therapy among HIV-1 infected persons in developing countries.

Validation of a modified commercial enzyme-linked immunoassay for detection of human immunodeficiency virus type 1 immunoglobulin G antibodies in saliva.

This study was performed to evaluate the performance of a saliva collection device (OmniSal) and an enzyme-linked immunoassay (EIA) designed for use on serum samples (Detect HIV1/2) to detect human immunodeficiency virus type 1 (HIV-1) antibodies in the saliva of high-risk women in Mombasa, Kenya. The results of the saliva assay were compared to a "gold standard" of a double-EIA testing algorithm performed on serum. Individuals were considered HIV-1 seropositive if their serum tested positive for antibodies to HIV-1 by two different EIAs. The commercial serum-based EIA was modified to test the saliva samples by altering the dilution and lowering the cutoff point of the assay. Using the saliva sample, the EIA correctly identified 102 of the 103 seropositive individuals, yielding a sensitivity of 99% (95% confidence interval [CI], 94 to 100%), and 96 of the 96 seronegative individuals, yielding a specificity of 100% (95% CI, 95 to 100%). In this high-risk population, the positive predictive value of the assay was 100% and the negative predictive value was 99%. We conclude that HIV-1 antibody testing of saliva samples collected with this device and tested by this EIA is of sufficient sensitivity and specificity to make this protocol useful in epidemiological studies.

Treatment of cervicitis is associated with decreased cervical shedding of HIV-1.

OBJECTIVE: To determine whether cervical mucosal shedding of HIV-1 RNA and HIV-1 infected cells decreases following successful treatment of cervicitis. DESIGN: Prospective interventional study. SETTING: Sexually Transmitted Infections Clinic, Coast Provincial General Hospital, Mombasa, Kenya. PARTICIPANTS: Thirty-six HIV-1 seropositive women with cervicitis: 16 with Neisseria gonorrhoeae, seven with Chlamydia trachomatis, and 13 with non-specific cervicitis. INTERVENTIONS: Treatment of cervicitis. MAIN OUTCOME MEASURES: Levels of total (cell-free and cell-associated) HIV-1 RNA and presence of HIV-1 DNA (a marker for infected cells) in cervical secretions before and after resolution of cervicitis. RESULTS: After treatment of cervicitis, the median HIV-1 RNA concentration in cervical secretions was reduced from 4.05 to 3.24 log10 copies/swab (P = 0.001). Significant decreases in cervical HIV-1 RNA occurred in the subgroups with N. gonorrhoeae (3.94 to 3.28 log10 copies/swab; P = 0.02) and C. trachomatis (4.21 to 3.19 log10 copies/swab; P = 0.02). Overall, the prevalence of HIV-1 infected cells in cervical secretions also decreased after treatment, from 67% to 42% (odds ratio, 2.8; 95% confidence interval, 1.3-6.0; P = 0.009). Detection of infected cells was associated with higher mean HIV-1 RNA levels (4.04 versus 2.99 log10 copies/swab; P< 0.0001). CONCLUSIONS: Effective treatment of cervicitis resulted in significant decreases in shedding of HIV-1 virus and infected cells in cervical secretions. Treatment of sexually transmitted diseases may be an important means of decreasing the infectivity of HIV-1 seropositive women by reducing exposure to HIV-1 in genital secretions.

Trends in HIV-1 incidence in a cohort of prostitutes in Kenya: implications for HIV-1 vaccine efficacy trials.

BACKGROUND: Accurate predictions of HIV-1 incidence in potential study populations are essential for designing HIV-1 vaccine efficacy trials. Little information is available on the estimated incidence of HIV-1 in such populations, especially information on incidence over time and incidence while participating in risk-reduction programs. OBJECTIVES: To examine time trends in HIV-1 incidence in a vaccine preparedness cohort. DESIGN: Prospective cohort study of female prostitutes in Mombasa, Kenya. METHODS: HIV-1 incidence was determined using open and closed cohort designs. Generalized estimating equations were used to model HIV-1 and sexually transmitted disease (STD) incidence and sexual risk behaviors over time. RESULTS: When analyzed as a closed cohort, HIV-1 incidence declined 10-fold during 3 years of follow-up (from 17.4 to 1.7 cases/100 person-years; p <.001). More than 50% of the cases of HIV-1 occurred during the first 6 months after enrollment, and 73% during the first 12 months. When analyzed as an open cohort, HIV-1 incidence density fell during the first 4 calendar years, influenced by accumulation of lower risk participants and variations in study recruitment. Significant declines occurred in both STD incidence and high-risk sexual behaviors during follow-up. CONCLUSIONS: This study documents a dramatic decline in the risk of HIV-1 infection while participating in a prospective cohort, with most seroconversions occurring within 1 year of enrollment. Variations in HIV-1 incidence within high-risk populations should be anticipated during the design of vaccine trials.

Primary human immunodeficiency virus type 1 infection: clinical manifestations among women in Mombasa, Kenya.

The occurrence of clinical manifestations associated with primary human immunodeficiency virus type 1 (HIV-1) infection was evaluated in a prospective cohort study of female sex workers in Mombasa, Kenya. Among 103 women who seroconverted to HIV-1, fever, vomiting, diarrhea, headache, arthralgia, myalgia, skin rash, swollen lymph nodes, extrainguinal lymphadenopathy, inguinal lymphadenopathy, and vaginal candidiasis were noted significantly more frequently at visits in which seroconversion first became evident. Eighty-one percent of seroconverting women had >/=1 of these 11 symptoms or signs. Among 44% of the women, the acute illness was severe enough to prevent them from working. Having >/=2 of 6 selected symptoms and signs yielded a sensitivity of 51%, specificity of 83%, positive likelihood ratio of 3.2, and negative likelihood ratio of 0.5 for acute HIV-1 infection. The recognition of primary HIV-1-infection illness in high-risk populations and subsequent risk-reduction counseling could potentially reduce secondary HIV-1 transmission during this highly infectious period.

Gender differences in HIV-1 diversity at time of infection.

To develop an HIV-1 vaccine with global efficacy, it is important to identify and characterize the viruses that are transmitted, particularly to individuals living in areas of high incidence. Several studies have shown that virus from the blood of acutely infected adults was homogeneous, even when the virus population in the index case was genetically diverse. In contrast to those results with mainly male cohorts in America and Europe, in several cases a heterogeneous virus population has been found early in infection in women in Africa. Thus, we more closely compared the diversity of transmitted HIV-1 in men and women who became infected through heterosexual contact. We found that women from Kenya were often infected by multiple virus variants, whereas men from Kenya were not. Moreover, a heterogeneous virus was present in the women before their seroconversion, and in each woman it was derived from a single index case, indicating that diversity was most likely to be the result of transmission of multiple variants. Our data indicate that there are important differences in the transmitted virus populations in women and men, even when cohorts from the same geographic region who are infected with the same subtypes of HIV-1 are compared.

Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition.

A prospective cohort study was conducted to examine the relationship between vaginal colonization with lactobacilli, bacterial vaginosis (BV), and acquisition of human immunodeficiency virus type 1 (HIV-1) and sexually transmitted diseases in a population of sex workers in Mombasa, Kenya. In total, 657 HIV-1-seronegative women were enrolled and followed at monthly intervals. At baseline, only 26% of women were colonized with Lactobacillus species. During follow-up, absence of vaginal lactobacilli on culture was associated with an increased risk of acquiring HIV-1 infection (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.2-3.5) and gonorrhea (HR, 1.7; 95% CI, 1.1-2.6), after controlling for other identified risk factors in separate multivariate models. Presence of abnormal vaginal flora on Gram's stain was associated with increased risk of both HIV-1 acquisition (HR, 1.9; 95% CI, 1.1-3.1) and Trichomonas infection (HR, 1.8; 95% CI, 1.3-2.4). Treatment of BV and promotion of vaginal colonization with lactobacilli should be evaluated as potential interventions to reduce a woman's risk of acquiring HIV-1, gonorrhea, and trichomoniasis.

Effect of circumcision on incidence of human immunodeficiency virus type 1 and other sexually transmitted diseases: a prospective cohort study of trucking company employees in Kenya.

To determine the effect of circumcision status on acquisition of human immunodeficiency virus (HIV) type 1 and other sexually transmitted diseases, a prospective cohort study of 746 HIV-1-seronegative trucking company employees was conducted in Mombasa, Kenya. During the course of follow-up, 43 men acquired HIV-1 antibodies, yielding an annual incidence of 3.0%. The annual incidences of genital ulcers and urethritis were 4.2% and 15.5%, respectively. In multivariate analysis, after controlling for demographic and behavioral variables, uncircumcised status was an independent risk factor for HIV-1 infection (hazard rate ratio [HRR=4.0; 95% confidence interval [CI], 1.9-8.3) and genital ulcer disease (HRR=2.5; 95% CI, 1.1-5.3). Circumcision status had no effect on the acquisition of urethral infections and genital warts. In this prospective cohort of trucking company employees, uncircumcised status was associated with increased risk of HIV-1 infection and genital ulcer disease, and these effects remained after controlling for potential confounders.

Cofactors for the acquisition of HIV-1 among heterosexual men: prospective cohort study of trucking company workers in Kenya.

OBJECTIVE: To determine the prevalence, incidence, and correlates of HIV-1 infection in a cohort of east African trucking company employees. METHODS: HIV-1-seronegative trucking company employees were enrolled in a prospective cohort study and evaluated at 3 monthly intervals for HIV-1 seroconversion, sexually transmitted diseases, and sexual behavior. RESULTS: The baseline seroprevalence of HIV-1 among 1500 trucking company employees was 17.8%. Among 752 HIV-1-seronegative men who were followed, the HIV-1 annual seroincidence was 3.1%. In univariate analysis, HIV-1 acquisition was associated with age under 25 years, 10 years or less of sexual activity, occupation as a driver/driver's assistant, occupational travel for more than 14 days per month, religion other than Christian or Muslim, uncircumcised status, sex with a prostitute, sex with a girlfriend/casual partner, extramarital sex, and enrollment seropositivity to Treponema pallidum, Haemophilus ducreyi, and Herpes simplex virus type 2 (all P values < or = 0.05). Using multivariate analysis, HIV-1 acquisition was independently associated with 10 years or less of sexual activity (hazard rate ratio (HRR) 2.0, 95% confidence interval (CI) 1.0-4.3), occupation as a driver/driver's assistant (HRR 3.9, 95% CI 1.7-9.0), religion other than Christian or Muslim (HRR 6.1, 95% CI 1.4-25.7), uncircumcised status (HRR 2.3, 95% CI 1.0-5.0), and unprotected sex with a prostitute (HRR 2.8, 95% CI 1.1-7.0). CONCLUSIONS: Trucking company employees had a high HIV-1 seroprevalence rate at enrollment and a high HIV-1 seroincidence during follow-up. Risk factors for HIV-1 seroconversion included years of sexual activity, occupation, religion, uncircumcised status, and unprotected sex with a prostitute. This population is an appropriate target for HIV-1 prevention trials and behavioral interventions.

Studies of human immunodeficiency virus type 1 mucosal viral shedding and transmission in Kenya.

If human immunodeficiency virus type 1 (HIV-1) vaccines are to be highly effective, it is essential to understand the virologic factors that contribute to HIV-1 transmission. It is likely that transmission is determined, in part, by the genotype or phenotype (or both) of infectious virus present in the index case, which in turn will influence the quantity of virus that may be exchanged during sexual contact. Transmission may also depend on the fitness of the virus for replication in the exposed individual, which may be influenced by whether a virus encounters a target cell that is susceptible to infection by that specific variant. Of interest, our data suggest that the complexity of the virus that is transmitted may be different in female and male sexual exposures.

Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1.

To examine associations between method of contraception, sexually transmitted diseases (STDs), and incident human immunodeficiency virus type 1 (HIV-1) infection, a prospective observational cohort study was done among female sex workers attending a municipal STD clinic in Mombasa, Kenya. Demographic and behavioral factors significantly associated with HIV-1 infection included type of workplace, condom use, and parity. In multivariate models, vulvitis, genital ulcer disease, vaginal discharge, and Candida vaginitis were significantly associated with HIV-1 seroconversion. Women who used depo medroxyprogesterone acetate (DMPA) had an increased incidence of HIV-1 infection (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.4-3.4). In a multivariate model controlling for demographic and exposure variables and biologic covariates, the adjusted HR for HIV-1 infection among DMPA users was 2.0 (CI, 1.3-3.1). There was a trend for an association between use of high-dose oral contraceptive pills and HIV-1 acquisition (HR, 2.6; CI, 0.8-8.5).