Catherine A. Koss

A systematic review of epidemiologic studies assessing condom use and risk of syphilis.

Background: Although systematic reviews of epidemiologic studies have been conducted for condom use and the risk of several sexually transmitted diseases, there have been no such reviews for condom use and syphilis. Methods: A systematic literature review of epidemiologic studies published from 1972 to 2008 was conducted to evaluate study methods and measures of association reported for condom use and risk of syphilis. Results: All 12 included studies had significant methodologic limitations. Nine (75%) studies were cross-sectional. Although 11 (92%) studies assessed consistent condom use, no studies assessed correct use or condom use problems, nor did any document exposure to a partner infected with syphilis. Ten studies had insufficient information to distinguish prevalent from incident infections. Two studies that assessed both incident infection and consistent condom use suggested a reduced risk of syphilis with consistent condom use; 1 study was statistically significant. Conclusions: Significant methodologic limitations exist for all reviewed studies of syphilis and condom use. Among the 2 most rigorously designed studies, both suggested a reduced risk of syphilis with consistent condom use. Additional studies incorporating rigorous methods are needed to further assess the effect of condom use on risk of syphilis.

Generic Entry, Reformulations and Promotion of SSRIs in the US

BackgroundPrevious research has shown that a manufacturer’s promotional strategy for a brand name drug is typically affected by generic entry. However, little is known about how newer strategies to extend patent life, including product reformulation introduction or obtaining approval to market for additional clinical indications, influence promotion.ObjectiveTo examine the relationships among promotional expenditures, generic entry, reformulation entry and new indication approval.MethodsWe used quarterly data on national product-level promotional spending (including expenditures for physician detailing and direct-to-consumer advertising [DTCA], and the retail value of free samples distributed in physician offices) for selective serotonin reuptake inhibitors (SSRIs) over the period 1997–2004. We estimated econometric models of detailing, DTCA and total quarterly promotional expenditures as a function of the timing of generic entry, entry of new product formulations and US FDA approval for new clinical indications for existing medications in the SSRI class. Expenditures by pharmaceutical manufacturers for promotion of antidepressant medications was the main outcome measure.ResultsOver the period 1997–2004, there was considerable variation in the composition of promotional expenditures across the SSRIs. Promotional expenditures for the original brand molecule decreased dramatically when a reformulation of the molecule was introduced. Promotional spending (both total and detailing alone) for a specific molecule was generally lower after generic entry than before, although the effect of generic entry on promotional spending appears to be closely linked with the choice of product reformulation strategy pursued by the manufacturer. Detailing expenditures for Paxil® were increased after the manufacturer received FDA approval to market the drug for generalized anxiety disorder (GAD), while the likelihood of DTCA outlays for the drug was not changed. In contrast, FDA approval to market Paxil® and Zoloft® for social anxiety disorder (SAD) did not affect the manufacturers’ detailing expenditures but did result in a greater likelihood of DTCA outlays.ConclusionThe introduction of new product formulations appears to be a common strategy for attempting to extend market exclusivity for medications facing impending generic entry. Manufacturers who introduced a reformulation before generic entry shifted most promotion dollars from the original brand to the reformulation long before generic entry, and in some cases manufacturers appeared to target a particular promotion type for a given indication. Given the significant impact that pharmaceutical promotion has on demand for prescription drugs in the US, these findings have important implications for prescription drug spending and public health.

Investigation of Metronidazole Use during Pregnancy and Adverse Birth Outcomes

ABSTRACT To assess whether treatment with metronidazole during pregnancy is associated with preterm birth, low birth weight, or major congenital anomalies, we conducted chart reviews and an analysis of electronic data from a cohort of women delivering at an urban New York State hospital. Of 2,829 singleton/mother pairs, 922 (32.6%) mothers were treated with metronidazole for clinical indications, 348 (12.3%) during the first trimester of pregnancy and 553 (19.5%) in the second or third trimester. There were 333 (11.8%) preterm births, 262 (9.3%) infants of low birth weight, and 52 infants (1.8%) with congenital anomalies. In multivariable analysis, no association was found between metronidazole treatment and preterm birth (odds ratio [OR], 1.02 [95% confidence interval [CI], 0.80 to 1.32]), low birth weight (OR, 1.05 [95% CI, 0.77 to 1.43]), or treatment in the first trimester and congenital anomalies (OR, 0.86 [0.30 to 2.45]). We found no association between metronidazole treatment during the first or later trimesters of pregnancy and preterm birth, low birth weight, or congenital anomalies.

Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy.

Background:Protease inhibitor–based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART. Methods:This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12–28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim–sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression. Results:Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth. Conclusions:LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Hair Concentrations of Antiretrovirals Predict Viral Suppression in HIV-Infected Pregnant and Breastfeeding Ugandan Women

Objective:Hair concentrations are a noninvasive measure of cumulative antiretroviral exposure and the strongest predictor of viral suppression in large cohorts of nonpregnant patients. We examined hair concentrations of antiretrovirals in relation to virologic outcomes in pregnant and breastfeeding women for the first time. Design and methods:The Prevention of Malaria and HIV Disease in Tororo trial (NCT00993031) enrolled HIV-infected pregnant Ugandan women at 12–28 weeks gestation who were randomized to lopinavir or efavirenz-based antiretroviral therapy (ART). Small hair samples were collected at 30–34 weeks gestation and 10–25 weeks postpartum. Efavirenz and lopinavir hair concentrations were measured via liquid chromatography/tandem mass spectrometry. Multivariate logistic regression models examined predictors of viral suppression (HIV-1 RNA ⩽400 copies/ml) at delivery and 24 weeks postpartum. Results:Among 325 women, median CD4+ cell count was 366 cells/&mgr;l (interquartile range 270–488) at ART initiation. Mean self-reported 3-day adherence was greater than 97% in each arm. Viral suppression was achieved by 98.0% (efavirenz) and 87.4% (lopinavir) at delivery. At 24 weeks postpartum, 92.5% (efavirenz) and 90.6% (lopinavir) achieved viral suppression; 88% of women were breastfeeding. In multivariate models including self-reported adherence and pretreatment HIV-1 RNA, antiretroviral hair concentrations were the strongest predictor of viral suppression at delivery [efavirenz: adjusted odds ratio (aOR) 1.86 per doubling in concentration, 95% confidence interval (CI) 1.14–3.1, P = 0.013; lopinavir: aOR 1.90, 95% CI 1.33–2.7, P = 0.0004] and 24 weeks postpartum (efavirenz: aOR 1.81, 95% CI 1.22–2.7, P = 0.003; lopinavir: aOR 1.53, 95% CI 1.05–2.2, P = 0.026). Conclusion:Antiretroviral hair concentrations represent an innovative tool that strongly predicts viral suppression among HIV-infected childbearing women during the critical periods of delivery and breastfeeding.

Efficacy and Safety of Lopinavir/ritonavir- versus Efavirenz-based Antiretroviral Therapy in HIV-Infected Pregnant Ugandan Women

Objective:Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4+ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda. Design:Randomized clinical trial. Methods:We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ⩽400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12–28 weeks gestation and any CD4+ cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum. Results:The median age of the 389 study participants was 29 years; median CD4+ cell count was 370 cells/&mgr;l. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P < 0.001). At 48 weeks postpartum, 91.0% of women on efavirenz and 88.4% on lopinavir/ritonavir had viral suppression (P = 0.49). Grade 1 or 2 gastrointestinal adverse events were higher among women on lopinavir/ritonavir versus efavirenz. Only two infants acquired HIV (both in the lopinavir/ritonavir arm), and HIV-free infant survival was similar between study arms: 92.9% (lopinavir/ritonavir) versus 97.2% (efavirenz) (P = 0.10). Conclusion:Virologic suppression at delivery was higher with an efavirenz versus lopinavir/ritonavir-based regimen. However, women in both arms achieved high levels of virologic suppression through 1 year postpartum and the risk of transmission to infants was low.

Antiretroviral Therapy With Efavirenz Accentuates Pregnancy‐Associated Reduction of Dihydroartemisinin‐Piperaquine Exposure During Malaria Chemoprevention

Dihydroartemisinin (DHA)‐piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz‐based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV‐uninfected pregnant women, in 27 HIV‐infected pregnant women receiving efavirenz, and in 30 HIV‐uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0‐8hr) were 50% and 47% lower, respectively, and piperaquine AUC0‐21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0‐8hr and piperaquine AUC0‐21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV‐uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed.

A clinical predictor score for 30-day mortality among HIV-infected adults hospitalized with pneumonia in Uganda

Background Pneumonia is a major cause of mortality among HIV-infected patients. Pneumonia severity scores are promising tools to assist clinicians in predicting patients’ 30-day mortality, but existing scores were developed in populations infected with neither HIV nor tuberculosis (TB) and include laboratory data that may not be available in resource-limited settings. The objective of this study was to develop a score to predict mortality in HIV-infected adults with pneumonia in TB-endemic, resource-limited settings. Methods We conducted a secondary analysis of data from a prospective study enrolling HIV-infected adults with cough ≥2 weeks and <6 months and clinically suspected pneumonia admitted to Mulago Hospital in Kampala, Uganda from September 2008 to March 2011. Patients provided two sputum specimens for mycobacteria, and those with Ziehl-Neelsen sputum smears that were negative for mycobacteria underwent bronchoscopy with inspection for Kaposi sarcoma and testing for mycobacteria and fungi, including Pneumocystis jirovecii. A multivariable best subsets regression model was developed, and one point was assigned to each variable in the model to develop a clinical predictor score for 30-day mortality. Results Overall, 835 patients were studied (mean age 34 years, 53.4% female, 30-day mortality 18.2%). A four-point clinical predictor score was identified and included heart rate >120 beats/minute, respiratory rate >30 breaths/minute, oxygen saturation <90%, and CD4 cell count <50 cells/mm3. Patients’ 30-day mortality, stratified by score, was: score 0 or 1, 12.6%, score 2 or 3, 23.4%, score 4, 53.9%. For each 1 point change in clinical predictor score, the odds of 30-day mortality increased by 65% (OR 1.65, 95% CI 1.39-1.96, p <0.001). Conclusions A simple, four-point scoring system can stratify patients by levels of risk for mortality. Rapid identification of higher risk patients combined with provision of timely and appropriate treatment may improve clinical outcomes. This predictor score should be validated in other resource-limited settings.

Intermittent Preventive Treatment With Dihydroartemisinin-Piperaquine for the Prevention of Malaria Among HIV-Infected Pregnant Women

Background Daily trimethoprim-sulfamethoxazole (TMP-SMX) and insecticide-treated nets remain the main interventions for prevention of malaria in human immunodeficiency virus (HIV)-infected pregnant women in Africa. However, antifolate and pyrethroid resistance threaten the effectiveness of these interventions, and new ones are needed. Methods We conducted a double-blinded, randomized, placebo-controlled trial comparing daily TMP-SMX plus monthly dihydroartemisinin-piperaquine (DP) to daily TMP-SMX alone in HIV-infected pregnant women in an area of Uganda where indoor residual spraying of insecticide had recently been implemented. Participants were enrolled between gestation weeks 12 and 28 and given an insecticide-treated net. The primary outcome was detection of active or past placental malarial infection by histopathologic analysis. Secondary outcomes included incidence of malaria, parasite prevalence, and adverse birth outcomes. Result All 200 women enrolled were followed through delivery, and the primary outcome was assessed in 194. There was no statistically significant difference in the risk of histopathologically detected placental malarial infection between the daily TMP-SMX plus DP arm and the daily TMP-SMX alone arm (6.1% vs. 3.1%; relative risk, 1.96; 95% confidence interval, .50-7.61; P = .50). Similarly, there were no differences in secondary outcomes. Conclusions Among HIV-infected pregnant women in the setting of indoor residual spraying of insecticide, adding monthly DP to daily TMP-SMX did not reduce the risk of placental or maternal malaria or improve birth outcomes. Clinical Trials Registration NCT02282293.

Viral Suppression and Retention in Care up to 5 Years After Initiation of Lifelong ART During Pregnancy (Option B+) in Rural Uganda

Background: Lifelong antiretroviral therapy (ART) is recommended for all HIV-infected pregnant women, but early studies suggest that women often drop out of care postpartum and data are limited on virologic outcomes. Methods: We evaluated viral suppression (primary outcome) and retention in care up to 5 years after ART initiation among HIV-infected women who started lifelong ART during pregnancy, irrespective of CD4 count, in a study in rural Uganda (NCT00993031). Participants were followed in the study for up to 1 year postpartum, then referred to clinics in surrounding communities. A random sample (N = 200) was invited to participate in a cross-sectional follow-up study after completing the trial, involving one visit for a questionnaire and pregnancy and HIV-1 RNA testing. Retention in care was defined as having attended an HIV clinic in the last 90 days. Logistic regression models were used to examine factors associated with viral suppression (HIV-1 RNA <400 copies/ml) at follow-up. Results: One hundred fifty women (75%) were successfully contacted for follow-up at a median of 4.2 years after starting ART; 135 were retained in care [90%, 95% confidence interval (CI): 84.0% to 94.3%] and 121 demonstrated viral suppression (80.7%, 95% CI: 73.4% to 86.7%). Women who had disclosed their HIV status to their primary partner had greater odds of viral suppression (adjusted odds ratio: 4.51, 95% CI: 1.02 to 19.8). Conclusions: High rates of viral suppression can be achieved up to 5 years after initiating ART during pregnancy among women retained in care. Interventions to facilitate disclosure may improve long-term outcomes among women who initiate ART during pregnancy under universal treatment.