Transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is ongoing in many communities throughout the United States. Although case-based and syndromic surveillance are critical for monitoring the pandemic, these systems rely on persons obtaining testing or reporting a COVID-19-like illness. Using serologic tests to detect the presence of SARS-CoV-2 antibodies is an adjunctive strategy that estimates the prevalence of past infection in a population. During April 28-May 3, 2020, coinciding with the end of a statewide shelter-in-place order, CDC and the Georgia Department of Public Health conducted a serologic survey in DeKalb and Fulton counties in metropolitan Atlanta to estimate SARS-CoV-2 seroprevalence in the population. A two-stage cluster sampling design was used to randomly select 30 census blocks in each county, with a target of seven participating households per census block. Weighted estimates were calculated to account for the probability of selection and adjusted for age group, sex, and race/ethnicity. A total of 394 households and 696 persons participated and had a serology result; 19 (2.7%) of 696 persons had SARS-CoV-2 antibodies detected. The estimated weighted seroprevalence across these two metropolitan Atlanta counties was 2.5% (95% confidence interval [CI] = 1.4-4.5). Non-Hispanic black participants more commonly had SARS-CoV-2 antibodies than did participants of other racial/ethnic groups (p<0.01). Among persons with SARS-CoV-2 antibodies, 13 (weighted % = 49.9; 95% CI = 24.4-75.5) reported a COVID-19-compatible illness,* six (weighted % = 28.2; 95% CI = 11.9-53.3) sought medical care for a COVID-19-compatible illness, and five (weighted % = 15.7; 95% CI = 5.1-39.4) had been tested for SARS-CoV-2 infection, demonstrating that many of these infections would not have been identified through case-based or syndromic surveillance. The relatively low seroprevalence estimate in this report indicates that most persons in the catchment area had not been infected with SARS-CoV-2 at the time of the survey. Continued preventive measures, including social distancing, consistent and correct use of face coverings, and hand hygiene, remain critical in controlling community spread of SARS-CoV-2.

BACKGROUND: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance. METHODS: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively. RESULTS: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene. CONCLUSION: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies. Trial Registration ClinicalTrials.gov NCT03387631.

BACKGROUND: Mass drug administration (MDA) appears to be effective in reducing the risk of malaria parasitaemia. This study reports on programmatic coverage and compliance of MDA using artemisinin-based combination therapy (ACT) in four shehias (smallest administration unit) that had been identified as hotspots through Zanzibar's malaria case notification surveillance system. METHODS: Mass drug administration was done in four shehias selected on the basis of: being an established malaria hot spot; having had mass screening and treatment (MSaT) 2-6 weeks previously; and exceeding the epidemic alert threshold of 5 cases within a week even after MSaT. Communities were sensitized and MDA was conducted using a house-to-house approach. All household members, except pregnant women and children aged less than 2 months, were provided with ACT medicine. Two weeks after the MDA campaign, a survey was undertaken to investigate completion of ACT doses. RESULTS: A total of 8816 [97.1% of eligible; 95% confidence interval (CI) 96.8-97.5] people received ACT. During post MDA surveys, 2009 people were interviewed: 90.2% reported having completed MDA doses; 1.9% started treatment but did not complete dosage; 4.7% did not take treatment; 2.0% were absent during MDA and 1.2% were ineligible (i.e. infants <2 months and pregnant women). Main reasons for failure to complete treatment were experience of side-effects and forgetting to take subsequent doses. Failure to take treatment was mainly due to fear of side-effects, reluctance due to lack of malaria symptoms and caregivers forgetting to give medication to children. CONCLUSION: Mass drug administration for malaria was well accepted by communities at high risk of malaria in Zanzibar, with high participation and completion rates. Further work to investigate the potential of MDA in accelerating Zanzibar's efforts towards malaria elimination should be pursued.

BACKGROUND: Malaria in pregnancy (MiP) remains a major public health challenge in areas of high malaria transmission. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended to prevent the adverse consequences of MiP. The effectiveness of SP for IPTp may be reduced in areas where the dhps581 mutation (a key marker of high level SP resistance) is found; this mutation was previously reported to be common in the Tanga Region of northern Tanzania, but there are limited data from other areas. The frequency of molecular markers of SP resistance was investigated in malaria parasites from febrile patients at health centres (HC) in seven regions comprising the Lake and Southern Zones of mainland Tanzania as part of the ongoing efforts to generate national-wide data of SP resistance. METHODS: A cross-sectional survey was conducted in the outpatient departments of 14 HCs in seven regions from April to June, 2015. 1750 dried blood spot (DBS) samples were collected (117 to 160 per facility) from consenting patients with positive rapid diagnostic tests for malaria, and no recent (within past 2 months) exposure to SP or related drugs. DNA was extracted from the DBS, pooled by HC, and underwent pooled targeted amplicon deep sequencing to yield estimates of mutated parasite allele frequency at each locus of interest. RESULTS: The dhps540 mutation was common across all 14 sites, ranging from 55 to 98.4% of sequences obtained. Frequency of the dhps581 mutation ranged from 0 to 2.4%, except at Kayanga HC (Kagera Region, Lake Zone) where 24.9% of sequences obtained were mutated. The dhfr164 mutation was detected only at Kanyanga HC (0.06%). CONCLUSION: By pooling DNA extracts, the allele frequency of mutations in 14 sites could be directly determined on a single deep-sequencing run. The dhps540 mutant was very common at all locations. Surprisingly, the dhps581 was common at one health center, but rare in all the others, suggesting that there is geographic micro-heterogeneity in mutant distribution and that accurate surveillance requires inclusion of multiple sites. A better understanding of the effect of the dhps581 mutant on the efficacy of IPTp-SP is needed.

Successful clinical trials of antiretroviral pre-exposure prophylaxis (PrEP) to prevent HIV infection have been reported in heterosexual men and women, men who have sex with men (MSM), and injection drug users1. A daily oral drug regimen containing nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC) have been effective when participant adherence is high1. Analysis of PrEP dosing patterns estimate taking at least four TDF doses per week provides 96% protection from HIV infection and at least two doses per week provides 76% protection in MSM and transgender women2, though some estimate more frequent dosing in heterosexual women may be needed3. TDF and FTC require phosphorylation in HIV target cells to tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) to provide PrEP protection as competitive analogs of naturally occurring deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP), respectively. However, it is unclear if physiological conditions that increase dNTP concentrations can affect pharmacokinetics (PK) and pharmacodynamics (PD) of NRTIs. This may be particularly relevant when cellular deoxynucleoside triphosphate (dNTP) pools in HIV target cells increase in response to immune activation. Decreased ratios of phosphorylated NRTIs to their respective dNTPs have been associated with cell activation in vitro and in nonhuman primate studies4,5, yet this observation remains unexplored in PK and PD studies that measured intracellular drug6-8. The study presented here compared dATP and dCTP concentrations to TFV-DP and FTC-TP in peripheral blood mononuclear cell (PBMCs) of persons using daily oral Truvada™ during a successful HIV PrEP study. We further examined if variations among intracellular drug:dNTP ratios were related to lymphocyte activation.

BACKGROUND: Results of the randomised, double-blind, placebo-controlled Bangkok Tenofovir Study (BTS) showed that taking tenofovir daily as pre-exposure prophylaxis (PrEP) can reduce the risk of HIV infection by 49% in people who inject drugs. In an extension to the trial, participants were offered 1 year of open-label tenofovir. We aimed to examine the demographic characteristics, drug use, and risk behaviours associated with participants' uptake of and adherence to PrEP. METHODS: In this observational, open-label extension of the BTS (NCT00119106), non-pregnant, non-breastfeeding, HIV-negative BTS participants, all of whom were current or previous injecting drug users at the time of enrolment in the BTS, were offered daily oral tenofovir (300 mg) for 1 year at 17 Bangkok Metropolitan Administration drug-treatment clinics. Participant demographics, drug use, and risk behaviours were assessed at baseline and every 3 months using an audio computer-assisted self-interview. HIV testing was done monthly and serum creatinine was assessed every 3 months. We used logistic regression to examine factors associated with the decision to take daily tenofovir as PrEP, the decision to return for at least one PrEP follow-up visit, and greater than 90% adherence to PrEP. FINDINGS: Between Aug 1, 2013, and Aug 31, 2014, 1348 (58%) of the 2306 surviving BTS participants returned to the clinics, 33 of whom were excluded because they had HIV (n=27) or grade 2-4 creatinine results (n=6). 798 (61%) of the 1315 eligible participants chose to start open-label PrEP and were followed up for a median of 335 days (IQR 0-364). 339 (42%) participants completed 12 months of follow-up; 220 (28%) did not return for any follow-up visits. Participants who were 30 years or older (odds ratio [OR] 1.8, 95% CI 1.4-2.2; p<0.0001), injected heroin (OR 1.5, 1.1-2.1; p=0.007), or had been in prison (OR 1.7, 1.3-2.1; p<0.0001) during the randomised trial were more likely to choose PrEP than were those without these characteristics. Participants who reported injecting heroin or being in prison during the 3 months before open-label enrolment were more likely to return for at least one open-label follow-up visit than those who did not report injecting heroin (OR 3.0, 95 % CI 1.3-7.3; p=0.01) or being in prison (OR 2.3, 1.4-3.7; p=0.0007). Participants who injected midazolam or were in prison during open-label follow-up were more likely to be greater than 90% adherent than were those who did not inject midazolam (OR 2.2, 95% CI 1.2-4.3; p=0.02) or were not in prison (OR 4.7, 3.1-7.2; p<0.0001). One participant tested positive for HIV, yielding an HIV incidence of 2.1 (95% CI 0.05-11.7) per 1000 person-years. No serious adverse events related to tenofovir use were reported. INTERPRETATION: More than 60% of returning, eligible BTS participants started PrEP, which indicates that a substantial proportion of PWID who are knowledgeable about PrEP might be interested in taking it. Participants who had injected heroin or been in prison were more likely to choose to take PrEP, suggesting that participants based their decision to take PrEP, at least in part, on their perceived risk of incident HIV infection. FUNDING: US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.

OBJECTIVE: Among participants of a clinical trial to test the efficacy of tenofovir/emtricitabine in protecting heterosexual men and women living in Botswana from HIV infection, determine 1) if sexual risk behavior, specifically condomless sex acts and number of sex partners, changed over time, 2) factors associated with condomless sex acts and number of sex partners and 3) the effect of participant treatment arm perception on risk behavior to address the possibility of risk compensation. METHODS: A longitudinal modeling of rates of risk behaviors was used to determine if the rate of condomless sex acts (#acts/person) and rate of sex partners (#partners/person) changed over time and which factors were associated with behavior change. RESULTS: 1200 participants were analyzed over 1 year. There was a 25% decrease in the rate of sex partners among participants sexually active in the last 30 days. The rate of reported condomless sex acts was greater for males (RR=1.34, CI=1.07-1.67) and participants whose sexual debut in years was ≤ 15 years of age (RR=1.65, CI=1.14-2.38) and 16-17 (RR=1.68, CI=1.22-2.31) compared to ≥20 years. Rate of reported sex partners was greater for males (RR=3.67, CI=2.86-4.71) and participants whose age at sexual debut in years was ≤15 (RR=2.92, CI=2.01-4.22) and 16-17 (RR=2.34, CI=1.69-3.24) compared to ≥20. There was no effect of participant treatment arm perception on risk behavior. CONCLUSIONS: Our study of PrEP to prevent HIV infection found no evidence of risk compensation which may have been due to participants' motivations to reduce their risk behaviors and risk-reduction counseling.

We describe HIV-1 evolutionary dynamics in the four participants from the TDF2-PrEP trial who became HIV-1-infected while prescribed FTC/TDF. At seroconversion, virus diversity in the 2 participants with detectable drug was only 0.05% (95% CI=0.04-0.06) and 0.07% (0.06-0.08) compared to 2.25% (1.95-2.6) and 0.42% (0.36-0.49) in those with no detectable drug, and 0.07%-0.69% in placebo recipients (p>0.5). At 10 months, diversity in adherent participants was only 0.37% (0.31-0.41) and 0.86% (0.82-0.90) compared to 0.5%-1.7% among participants that did not take FTC/TDF (p>0.5). Although limited by the small number of infections that reduced the power to detect differences, we found that sequences from seroconverters with detectable drug were more homogeneous than those from placebo or non-adherent seroconverters.

BACKGROUND: Rapid easy-to-use HIV tests offer opportunities to increase HIV testing among populations at risk of infection. We used the OraQuick Rapid HIV-1/2 antibody test (OraQuick) in the Bangkok Tenofovir Study, an HIV pre-exposure prophylaxis trial among people who inject drugs. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial. We tested participants' oral fluid for HIV using OraQuick monthly and blood using a nucleic-acid amplification test (NAAT) every 3 months. We used Kaplan-Meier methods to estimate the duration from a positive HIV NAAT until the mid-point between the last non-reactive and first reactive oral fluid test and proportional hazards to examine factors associated with the time until the test was reactive. RESULTS: We screened 3678 people for HIV using OraQuick. Among 447 with reactive results, 436 (97.5%) were confirmed HIV-infected, 10 (2.2%) HIV-uninfected, and one (0.2%) had indeterminate results. Two participants with non-reactive OraQuick results were, in fact, HIV-infected at screening yielding 99.5% sensitivity, 99.7% specificity, a 97.8% positive predictive value, and a 99.9% negative predictive value. Participants receiving tenofovir took longer to develop a reactive OraQuick (191.8 days) than participants receiving placebo (16.8 days) (p = 0.02) and participants infected with HIV CRF01_AE developed a reactive OraQuick earlier than participants infected with other subtypes (p = 0.04). DISCUSSION: The oral fluid HIV test performed well at screening, suggesting it can be used when rapid results and non-invasive tools are preferred. However, participants receiving tenofovir took longer to develop a reactive oral fluid test result than those receiving placebo. Thus, among people using pre-exposure prophylaxis, a blood-based HIV test may be an appropriate choice. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119106.

To reduce obesity prevalence, public health practitioners are intervening to change health behaviors as well as the policies, systems, and environments (PSEs) that support healthy behaviors. Although the number of recommended PSE intervention strategies continues to grow, limited guidance is available on how to implement those strategies in practice. This article describes the University of North Carolina at Chapel Hill, Center for Training and Research Translation's (Center TRT's) approach to reviewing, translating, and disseminating practitioner-developed interventions, with the goal of providing more practical guidance on how to implement PSE intervention strategies in real-world practice. As of August 2014, Center TRT had disseminated 30 practice-based PSE interventions. This article provides an overview of Center TRT's process for reviewing, translating, and disseminating practice-based interventions and offers key lessons learned during the nine years that Center TRT has engaged in this work.

OBJECTIVE: To describe participant adherence to daily oral tenofovir in an HIV preexposure prophylaxis (PrEP) trial, examine factors associated with adherence, and assess the impact of adherence on the risk of HIV infection. DESIGN: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial conducted among people who inject drugs, 2005-2012. METHODS: Participants chose daily visits or monthly visits. Study nurses observed participants swallow study drug and both initialed a diary. We assessed adherence using the diary. We examined adherence by age group and sex and used logistic regression to evaluate demographics and risk behaviors as predictors of adherence and Cox regression to assess the impact of adherence on the risk of HIV infection. RESULTS: A total of 2413 people enrolled and contributed 9665 person-years of follow-up (mean 4.0 years, maximum 6.9 years). The risk of HIV infection decreased as adherence improved, from 48.9% overall to 83.5% for those with at least 97.5% adherence. In multivariable analysis, men were less adherent than women (P = 0.006) and participants 20-29 years old (P < 0.001) and 30-39 years old (P = 0.01) were less adherent than older participants. Other factors associated with poor adherence included incarceration (P = 0.02) and injecting methamphetamine (P = 0.04). CONCLUSION: In this HIV PrEP trial among people who inject drugs, improved adherence to daily tenofovir was associated with a lower risk of HIV infection. This is consistent with trials among MSM and HIV-discordant heterosexual couples and suggests that HIV PrEP can provide a high level of protection from HIV infection.

OBJECTIVES: We examined the causes of hospitalization and death of people who inject drugs participating in the Bangkok Tenofovir Study, an HIV preexposure prophylaxis trial. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial conducted during 2005 to 2012 among 2413 people who inject drugs. We reviewed medical records to define the causes of hospitalization and death, examined participant characteristics and risk behaviors to determine predictors of death, and compared the participant mortality rate with the rate of the general population of Bangkok, Thailand. RESULTS: Participants were followed an average of 4 years; 107 died: 22 (20.6%) from overdose, 13 (12.2%) from traffic accidents, and 12 (11.2%) from sepsis. In multivariable analysis, older age (40-59 years; P = .001), injecting drugs (P = .03), and injecting midazolam (P < .001) were associated with death. The standardized mortality ratio was 2.9. CONCLUSIONS: People who injected drugs were nearly 3 times as likely to die as were those in the general population of Bangkok and injecting midazolam was independently associated with death. Drug overdose and traffic accidents were the most common causes of death, and their prevention should be public health priorities.

This study examined study product adherence and its determinants in the Botswana oral pre-exposure prophylaxis efficacy trial. Among the 1,219 participants, the mean adherence by pill count and 3-day self-report was 94 % for each. In multivariable models, pill count adherence was significantly associated with adverse events (nausea, dizziness, vomiting) (RR 0.98 95 % CI 0.98-1.00; p = 0.03) and side effect concerns (RR 0.98 95 % CI 0.96-0.99; p = 0.01). Self-reported adherence was significantly associated with having an HIV-positive partner (RR 1.02 95 % CI 1.00-1.04; p = 0.02) and Francistown residence (RR 0.98 95 % CI 0.96, 0.99; p = 0.0001). Detectable drug concentrations showed modest associations with self-report and pill count adherence, and drug levels were higher among those self-reporting 100 % adherence than those reporting <100 %. Most common adherence barriers involved refill delays and other logistic challenges; cellphone alarm reminder use was the most common facilitator.

PURPOSE: To determine whether a bacteriophage antimicrobial-lock technique can reduce bacterial colonization and biofilm formation on indwelling central venous catheters in a rabbit model. MATERIALS AND METHODS: Cuffed central venous catheters were inserted into the jugular vein of female New Zealand White rabbits under image guidance. Catheters were inoculated for 24 hours with broth culture of methicillin-sensitive Staphylococcus aureus. The inoculum was aspirated, and rabbits were randomly assigned to two equal groups for 24 hours: (i) untreated controls (heparinized saline lock), (ii) bacteriophage antimicrobial-lock (staphylococcal bacteriophage K, propagated titer > 108/mL). Blood cultures were obtained via peripheral veins, and the catheters were removed for quantitative culture and scanning electron microscopy. RESULTS: Mean colony-forming units (CFU) per cm2 of the distal catheter segment, as a measure of biofilm, were significantly decreased in experimental animals compared with controls (control, 1.2 x 105 CFU/cm2; experimental, 7.6 x 103; P = .016). Scanning electron microscopy demonstrated that biofilms were present on the surface of five of five control catheters but only one of five treated catheters (P = .048). Blood culture results were not significantly different between the groups. CONCLUSIONS: In a rabbit model, treatment of infected central venous catheters with a bacteriophage antimicrobial-lock technique significantly reduced bacterial colonization and biofilm presence. Our data represent a preliminary step toward use of bacteriophage therapy for prevention and treatment of central venous catheter-associated infection.

BACKGROUND: Tenofovir disoproxil fumarate (tenofovir) has been associated with renal dysfunction in people infected with HIV receiving combination antiretroviral treatment. We reviewed data from an HIV pre-exposure prophylaxis trial to determine if tenofovir use was associated with changes in renal function in an HIV-uninfected population. METHODS: During the trial, 2413 HIV-uninfected people who inject drugs were randomized to receive tenofovir or placebo. We assessed the renal function of trial participants with the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations using t-tests for cross-sectional analysis and linear regression for longitudinal analysis. RESULTS: Creatinine clearance and glomerular filtration rate (GFR) results were lower at 24, 36, 48, and 60 months in the tenofovir group compared with the placebo group. Results declined more in the tenofovir group than in the placebo group during follow-up using the Cockcroft-Gault (p<0.001) and CKD-EPI (p=0.007) equations, but not MDRD (p=0.12). Creatinine clearance measured when study drug was stopped was lower in the tenofovir than placebo group (p<0.001); but the difference resolved when tested a median of 20 months later (p=0.12). CONCLUSION: We found small, but significant decreases in cross-sectional measures of creatinine clearance and GFR in the tenofovir group compared with the placebo group and modest differences in downward trends in longitudinal analysis using the Cockcroft-Gault and CKD-EPI equations. These results suggest that with baseline assessments of renal function and routine monitoring of creatinine clearance during follow-up, tenofovir can be used safely for HIV pre-exposure prophylaxis.

INTRODUCTION: Accurate clinical laboratory reference values derived from a local or regional population base are required to correctly interpret laboratory results. In Botswana, most reference intervals used to date are not standardized across clinical laboratories and are based on values derived from populations in the United States or Western Europe. METHODS: We measured 14 hematologic and biochemical parameters of healthy young adults screened for participation in the Botswana HIV Pre-exposure Prophylaxis Study using tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (TDF2 Study). Reference intervals were calculated using standard methods, stratified by gender, and compared with the site-derived reference values used for the TDF2 study (BOTUSA ranges), the Division of AIDS (DAIDS) Grading Table for Adverse Events, the Botswana public health laboratories, and other regional references. RESULTS: Out of 2533 screened participants, 1786 met eligibility criteria for participation in study and were included in the analysis. Our reference values were comparable to those of the Botswana public health system except for amylase, blood urea nitrogen (BUN), phosphate, total and direct bilirubin. Compared to our reference values, BOTUSA reference ranges would have classified participants as out of range for some analytes, with amylase (50.8%) and creatinine (32.0%) producing the highest out of range values. Applying the DAIDS toxicity grading system to the values would have resulted in 45 and 18 participants as having severe or life threatening values for amylase and hemoglobin, respectively. CONCLUSION: Our reference values illustrate the differences in hematological and biochemical analyte ranges between African and Western populations. Thus, the use of western-derived reference laboratory values to screen a group of Batswana adults resulted in many healthy people being classified as having out-of-range blood analytes. The need to establish accurate local or regional reference values is apparent and we hope our results can be used to that end in Botswana.

INTRODUCTION: HIV spread rapidly among people who inject drugs in Bangkok in the late 1980s. In recent years, changes in drug use and HIV-associated risk behaviors have been reported. We examined data from the Bangkok Tenofovir Study, an HIV pre-exposure prophylaxis trial conducted among people who inject drugs, to assess participant risk behavior and drug use, and to identify risk factors for HIV infection. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial. HIV status was assessed monthly and risk behavior every 3 months. We used generalized estimating equations logistic regression to model trends of injecting, needle sharing, drugs injected, incarceration, and sexual activity reported at follow-up visits; and proportional hazards models to evaluate demographic characteristics, sexual activities, incarceration, drug injection practices, and drugs injected during follow-up as predictors of HIV infection. RESULTS: The proportion of participants injecting drugs, sharing needles, and reporting sex with more than one partner declined during follow-up (p<0.001). Among participants who reported injecting at enrollment, 801 (53.2%) injected methamphetamine, 559 (37.1%) midazolam, and 527 (35.0%) heroin. In multivariable analysis, young age (i.e., 20-29 years) (p = 0.02), sharing needles (p<0.001), and incarceration in prison (p = 0.002) were associated with incident HIV infection. Participants reporting sex with an opposite sex partner, live-in partner, casual partner, or men reporting sex with male partners were not at a significantly higher risk of HIV infection compared to those who did not report these behaviors. CONCLUSION: Reports of HIV-associated risk behavior declined significantly during the trial. Young age, needle sharing, and incarceration were independently associated with HIV infection. Sexual activity was not associated with HIV infection, suggesting that the reduction in HIV incidence among participants taking daily oral tenofovir compared to those taking placebo was due to a decrease in parenteral HIV transmission.

BACKGROUND: Tenofovir-emtricitabine (TDF-FTC) pre-exposure prophylaxis (PrEP) has been found to be effective for prevention of HIV infection in several clinical trials. Two studies of TDF PrEP among men who have sex with men showed slight bone mineral density (BMD) loss. We investigated the effect of TDF and the interaction of TDF and hormonal contraception on BMD among HIV-uninfected African men and women. METHOD: We evaluated the effects on BMD of using daily oral TDF-FTC compared to placebo among heterosexual men and women aged 18-29 years enrolled in the Botswana TDF2 PrEP study. Participants had BMD measurements at baseline and thereafter at 6-month intervals with dual-energy X-ray absorptiometry (DXA) scans at the hip, spine, and forearm. RESULTS: A total of 220 participants (108 TDF-FTC, 112 placebo) had baseline DXA BMD measurements at three anatomic sites. Fifteen (6.8%) participants had low baseline BMD (z-score of <-2.0 at any anatomic site), including 3/114 women (2.6%) and 12/106 men (11.3%) (p = 0.02). Low baseline BMD was associated with being underweight (p = 0.02), having high blood urea nitrogen (p = 0.02) or high alkaline phosphatase (p = 0.03), and low creatinine clearance (p = 0.04). BMD losses of >3.0% at any anatomic site at any time after baseline were significantly greater for the TDF-FTC treatment group [34/68 (50.0%) TDF-FTC vs. 26/79 (32.9%) placebo; p = 0.04]. There was a small but significant difference in the mean percent change in BMD from baseline for TDF-FTC versus placebo at all three sites at month 30 [forearm -0.84% (p = 0.01), spine -1.62% (p = 0.0002), hip -1.51% (p = 0.003)]. CONCLUSION: Use of TDF-FTC was associated with a small but statistically significant decrease in BMD at the forearm, hip and lumbar spine. A high percentage (6.8%) of healthy Batswana young adults had abnormal baseline BMD. Further evaluation is needed of the longer-term use of TDF in HIV-uninfected persons. TRIAL REGISTRATION: ClinicalTrials.gov NCT00448669.

We examined CD4 cell count and plasma viral load patterns among Botswana TDF/FTC Oral HIV Prophylaxis Trial (TDF2 study) participants who seroconverted, comparing participants assigned to receive tenofovir/emtricitabine with participants assigned to receive placebo. We also evaluated for antiretroviral drug resistance among the breakthrough HIV infections. Among nine seroconverters assigned to tenofovir/emtricitabine and 24 to placebo, there were no significant differences in their CD4 cell count or viral load profiles over time. Of the four participants who seroconverted on-study while receiving tenofovir/emtricitabine, none became infected as a result of drug-resistant HIV; moreover, no resistance mutations emerged following seroconversion.

BACKGROUND: Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20-60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00119106. FINDINGS: Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0.35 per 100 person-years) and 33 in the placebo group (0.68 per 100 person-years), indicating a 48.9% reduction in HIV incidence (95% CI 9.6-72.2; p=0.01). The occurrence of serious adverse events was much the same between the two groups (p=0.35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0.002). INTERPRETATION: In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs. FUNDING: US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.

OBJECTIVE: To evaluate for changes in sexual behaviors associated with daily pill-use among MSM participating in a PrEP trial. DESIGN: Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to receive tenofovir disoproxil fumarate or placebo at enrollment or after a 9-month delay and followed for 24 months. METHODS: 400 HIV-negative MSM reporting anal sex with a man in the past 12 months and meeting other eligibility criteria enrolled in San Francisco, Atlanta, and Boston. Sexual risk was assessed at baseline and quarterly visits using Audio Computer-Assisted Self-Interview. The association of pill-taking with sexual behavior was evaluated using logistic and negative-binomial regression for repeated measures. RESULTS: Overall indices of behavioral risk declined or remained stable during follow-up. Mean numbers of partners and proportion reporting unprotected anal sex (UAS) declined during follow-up (p<0.05), and mean UAS episodes remained stable. During the initial 9 months, changes in risk practices were similar in the group that began pills immediately vs. those in the delayed arm. These indices of risk did not differ significantly after initiation of pill-use in the delayed arm or continuation of study medication in the immediate arm. Use of poppers, amphetamines, and sexual performance-enhancing drugs were independently associated with one or more indices of sexual risk. CONCLUSIONS: There was no evidence of risk compensation among HIV-uninfected MSM in this clinical trial. Monitoring for risk compensation should continue now that PrEP has been shown to be efficacious in MSM and other populations and will be provided in open-label trials and other contexts.

OBJECTIVES: To evaluate the clinical safety of daily tenofovir disoproxil fumarate (TDF) among HIV-negative MSM. DESIGN: Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to immediate or delayed study drug (TDF [300mg orally/day] or placebo). METHODS: 400 healthy HIV-uninfected MSM reporting anal sex with another man within the previous 12 months enrolled in Atlanta, Boston, and San Francisco. HIV serostatus, clinical and laboratory adverse events, adherence (pill count, Medical Event Monitoring System, [MEMS] and self-report), sexual and other sociobehavioral data were assessed at 3-month intervals for 24 months. Primary outcomes were clinical safety, assessed by incidence of adverse events and laboratory abnormalities. RESULTS: Study drug was initiated by 373 (93%) participants (186 TDF, 187 placebo), of whom 325 (87%) completed the final study visit. Of 2,428 adverse events reported among 334 (90%) participants, 2,366 (97%) were mild or moderate in severity.Frequencies of commonly reported adverse events did not differ significantly between TDF and placebo arms. In multivariable analyses, back pain was more likely among TDF recipients (p=0.04); these reports were not associated with documented fractures or other objective findings. There were no Grade ≥3 creatinine elevations; Grade 1 and 2 creatinine increases were not associated with TDF receipt. Estimated percent of study drug doses taken was 92% by pill count and 77% by MEMS. Seven seroconversions occurred; 4 on placebo and 3 among delayed arm participants not yet on study drug. CONCLUSION: Daily oral TDF was well tolerated, with reasonable adherence. No significant renal concerns were identified.

PURPOSE OF REVIEW: To discuss the factors pertinent to the use of pre-exposure prophylaxis (PrEP) by at-risk heterosexuals in countries with generalized HIV epidemics. RECENT FINDINGS: PrEP will have the greatest prevention effect if targeted to those at highest risk, but identifying and engaging such persons is challenging. Serodiscordant couples account for a high proportion of new infections and are an appropriate target for PrEP, but the proportion of people in such relationships is small and outside partnerships are common. Differences in adherence coupled to pharmacology of the drugs may account for differences in efficacy seen in the trials. Mathematical modeling indicates that the benefits of PrEP in highly endemic settings outweigh the risk of induced viral resistance. Behavioral risk compensation was not observed in the trials, but current open-label studies will better determine if disinhibition will be an important problem. CONCLUSIONS: PrEP is a potentially useful HIV-prevention strategy for generalized heterosexual epidemics. Optimal implementation will require learning more about ways to improve acceptability and adherence and how best to deliver PrEP within the context of limited resource availability.

BACKGROUND: Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain. METHODS: We randomly assigned HIV-seronegative men and women to receive either tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or matching placebo once daily. Monthly study visits were scheduled, and participants received a comprehensive package of prevention services, including HIV testing, counseling on adherence to medication, management of sexually transmitted infections, monitoring for adverse events, and individualized counseling on risk reduction; bone mineral density testing was performed semiannually in a subgroup of participants. RESULTS: A total of 1219 men and women underwent randomization (45.7% women) and were followed for 1563 person-years (median, 1.1 years; maximum, 3.7 years). Because of low retention and logistic limitations, we concluded the study early and followed enrolled participants through an orderly study closure rather than expanding enrollment. The TDF-FTC group had higher rates of nausea (18.5% vs. 7.1%, P<0.001), vomiting (11.3% vs. 7.1%, P=0.008), and dizziness (15.1% vs. 11.0%, P=0.03) than the placebo group, but the rates of serious adverse events were similar (P=0.90). Participants who received TDF-FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF-FTC group who had had an unrecognized acute HIV infection at enrollment. In a modified intention-to-treat analysis that included the 33 participants who became infected during the study (9 in the TDF-FTC group and 24 in the placebo group; 1.2 and 3.1 infections per 100 person-years, respectively), the efficacy of TDF-FTC was 62.2% (95% confidence interval, 21.5 to 83.4; P=0.03). CONCLUSIONS: Daily TDF-FTC prophylaxis prevented HIV infection in sexually active heterosexual adults. The long-term safety of daily TDF-FTC prophylaxis, including the effect on bone mineral density, remains unknown. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health; TDF2 ClinicalTrials.gov number, NCT00448669 .).

BACKGROUND: The Bangkok Tenofovir Study was launched in 2005 to determine if pre-exposure prophylaxis with tenofovir will reduce the risk of HIV infection among injecting drug users (IDUs). We describe recruitment, screening, enrollment, and baseline characteristics of study participants and contrast risk behavior of Tenofovir Study participants with participants in the 1999-2003 AIDSVAX B/E Vaccine Trial. METHODS: The Bangkok Tenofovir Study is an ongoing, phase-3, randomized, double-blind, placebo-controlled, HIV pre-exposure prophylaxis trial of daily oral tenofovir. The Tenofovir Study and the Vaccine Trial were conducted among IDUs at 17 drug-treatment clinics in Bangkok. Tenofovir Study sample size was based on HIV incidence in the Vaccine Trial. Standardized questionnaires were used to collect demographic, risk behavior, and incarceration data. The Tenofovir Study is registered with ClinicalTrials.gov, number-NCT00119106. RESULTS: From June 2005 through July 2010, 4094 IDUs were screened and 2413 enrolled in the Bangkok Tenofovir Study. The median age of enrolled participants was 31 years (range, 20-59), 80% were male, and 63% reported they injected drugs during the 3 months before enrollment. Among those who injected, 53% injected methamphetamine, 37% midazolam, and 35% heroin. Tenofovir Study participants were less likely to inject drugs, inject daily, or share needles (all, p<0.001) than Vaccine Trial participants. DISCUSSION: The Bangkok Tenofovir Study has been successfully launched and is fully enrolled. Study participants are significantly less likely to report injecting drugs and sharing needles than participants in the 1999-2003 AIDSVAX B/E Vaccine Trial suggesting HIV incidence will be lower than expected. In response, the Bangkok Tenofovir Study enrollment was increased from 1600 to 2400 and the study design was changed from a defined 1-year follow-up period to an endpoint-driven design. Trial results demonstrating whether or not daily oral tenofovir reduces the risk of HIV infection among IDUs are expected in 2012.

As new HIV prevention tools are developed, researchers face a number of ethical and logistic questions about how and when to include novel HIV prevention strategies and tools in the standard prevention package of ongoing and future HIV prevention trials. Current Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO) guidance recommends that participants in prevention trials receive 'access to all state of the art HIV risk reduction methods', and that decisions about adding new tools to the prevention package be made in consultation with 'all relevant stakeholders'. The guidance, however, leaves open questions of both process and implementation. In March 2009, the Global Campaign for Microbicides, UNAIDS and the Centers for Disease Control and Prevention convened a consultation to develop practical answers to these questions. Fifty-nine diverse participants, including researchers, ethicists, advocates and policymakers, worked to develop consensus criteria on when to include new HIV prevention tools in future trials. Participants developed a set of questions to guide decision-making, including: whether the method has been recommended by international bodies or adopted at a national level; the size of the effect and weight of the evidence; relevance to the trial population; whether the tool has been approved or introduced in the trial country; whether adding the tool might lead to trial futility; outstanding safety issues and status of the trial. Further work is needed to develop, implement and evaluate approaches to facilitate meaningful stakeholder participation in this deliberative process.

HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.

In the absence of an effective vaccine, HIV continues to spread worldwide, emphasizing the need for new biomedical interventions to limit its transmission. Appreciation of the challenges that HIV has to face to initiate an infection mucosally has spurred interest in evaluating the use of antiretroviral drugs to prevent infection. Recent animal studies using macaques or humanized mice models of mucosal transmission of SIV or HIV have shown that daily or intermittent pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can exploit early virus vulnerabilities and effectively prevent establishment of infection. These preclinical findings have fueled interest in evaluating the safety and efficacy of PrEP in humans. We provide an overview of the rationale behind PrEP and discuss the next steps in PrEP research, including the need to better define the ability of current drugs to reach and accumulate in mucosal tissues and protect cells that are primary targets during early HIV infection.