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Background The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. Methods An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. Results We estimated that PrEP was highly protective (85%–96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%–88% efficacy) than in Harlem (62%–81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8–9 percentage points in Harlem and by 5–9 percentage points in Bangkok across regimens. Conclusions Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.

Regular HIV testing is required to ensure the safety of HIV pre-exposure prophylaxis (PrEP). We describe and discuss a series of false-positive HIV test results from an individual receiving PrEP. The expansion of PrEP will likely result in greater numbers of false-positive test results that may pose challenges for interpretation.

Self-reported adherence to pre-exposure prophylaxis (PrEP) has limitations, raising interest in pharmacologic monitoring. Drug concentrations in hair and dried blood spots (DBS) are used to assess long-term-exposure; hair shipment/storage occurs at room temperature. The iPrEx Open Label Extension collected DBS routinely, with opt-in hair collection; concentrations were measured with liquid chromatography/tandem mass spectrometry. In 806 hair-DBS pairs, tenofovir (TFV) hair levels and TFV diphosphate (DP) in DBS were strongly correlated (Spearman coefficient r = 0.734; P < .001), as were hair TFV/DBS emtricitabine (FTC) triphosphate (TP) (r = 0.781; P < .001); hair FTC/DBS TFV-DP (r = 0.74; P < .001); hair FTC/DBS FTC-TP (r = 0.587; P < .001). Drug detectability was generally concordant by matrix. Hair TFV/FTC concentrations correlate strongly with DBS levels, which are predictive of PrEP outcomes.

Antiretroviral drugs have demonstrated efficacy when used as preexposure prophylaxis (PrEP) for preventing human immunodeficiency virus (HIV) acquisition through sexual or intravenous exposure in uninfected men, women, and transgendered women [1–5]. A consistent finding among reported randomized, placebo-controlled trials testing oral and topical PrEP strategies is that efficacy is associated with drug exposure [6, 7]. In the iPrEx study, where the safety and efficacy of daily oral dosing of combination nucleoside/nucleotide reverse-transcriptase inhibitors (nRTI) emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) was tested in men and transgender women who have sex with men, a 44% reduction in infection incidence was seen in participants randomized to FTC/TDF compared with placebo [3], and a 99% reduction among those with blood FTC/TDF levels commensurate with daily dosing [8]. In contrast, in the Fem-PrEP and VOICE trials where product adherence was low, the use of oral TDF, TDF/FTC, or tenofovir (TFV) 1% vaginal gel did not significantly reduce HIV infections [9]. Decades of experience with therapeutic use of antiretroviral drugs have accumulated an extensive understanding of the causes and consequences of HIV drug resistance (DR), which emerges with suboptimal antiretroviral therapy (ART), including the dual nRTI regimens such as that recommended for PrEP [10–12]. If HIV infection occurred during suboptimal PrEP use, DR could be selected early in infection [13, 14]. In rhesus macaque studies investigating oral FTC/TDF PrEP, breakthrough infections following rectal exposure showed FTC-selected DR mutations M184V/I [15]. In people with unrecognized infection, antiretroviral use intended as PrEP is functionally postexposure prophylaxis (PEP), where DR can occur in breakthrough systemic infection [2–4, 16, 17]. Additionally, initial efforts administering single-dose nevirapine to mothers at birth for prevention of mother-to-child-transmission (MTCT) resulted in rapid emergence of drug-selected mutations in infected infants measured by population sequencing [18–22]. Ultrasensitive diagnostic assays revealed a substantially higher frequency of mothers and infants with minor variant DR [23–26]. These findings demonstrate that the use of antiretrovirals to prevent infection can select for DR when breakthrough infections occur, and warrant thorough and sensitive monitoring in PrEP studies. We report the results from comprehensive viral DR testing and drug exposure measurements in iPrEx seroconverters in a clinical trial setting. Clinical genotype and phenotype assays were performed to detect resistance in viral populations. We quantified minor variant FTC/TDF-selected mutations by deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR)–based assay that controls for target sequence polymorphisms and yields improved performance when testing isolates from diverse geographic locations [27–29]. The nature and frequency of DR mutations are presented in the context of concurrent systemic FTC/TDF exposure.

BACKGROUND: Delays to brain tumour diagnosis impacts on patient well-being, and may affect available treatment options and patient outcomes. Promoting earlier diagnosis is one of the top 10 clinical research priorities for the UK neuro-oncology community. Understanding the pathway from symptom onset to treatment, and how this varies between patients, is crucial to improving the diagnostic process. MATERIAL AND METHODS: A prospective cohort study of adult patients with imaging suspected intracranial tumour prior to neurosurgical treatment at a single neuro-oncology centre in South East Scotland, UK, between August 2016 and February 2018 was undertaken to provide contemporary and detailed information on clinical pathway to diagnosis and to explore factors leading to a prolonged diagnosis. Clinical pathway was described in accordance with Aarhus criteria. RESULTS: 180 consecutive consenting patients +/- carers with intracranial tumour were interviewed. 52% were female and mean age was 56.8 (SD 13.5) years. Glioblastoma multiforme (37.2%), meningioma (22.8%), cerebral metastases (15.6%) were the most common tumours. More prolonged time to diagnosis was associated with being female, single/divorced/widowed, non- seizure first symptom and presentation via general practice. 122 (65%) patients saw their GP at least once, while 38 (21%) had 3+ visits prior to diagnosis. 123 (68%) patients were finally diagnosed in an emergency department (ED), of which 83 (67.5%) self-presented to ED. “Non-focal” first symptom (adjusted OR=33.2, p=0.003) and female sex (aOR=4.7, p=0.02) were independent predictors of seeing a GP prior to ED admission. Seizure was the commonest symptom (n=47) leading to ED, however over half of these patients (n=26 (55.3%)), had previously complained of headache or non-focal symptoms such as memory or personality change prior to seizure. CONCLUSION: Only 65% of patients with brain tumours see their GP prior to diagnosis of a brain tumour, but >20% see the GP more than three times. GP presenting patients are more commonly female and have non-focal symptoms (e.g. headache/memory/personality change). More work needs to be done around the reasons why GPs do not recognise non-focal presentations or if there are system delays in hospital referral resulting in patients presenting in ED.

Although the epidemiology of transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations has been studied in a variety of settings [1–5], less is known about whether transmitted mutations persist without selection pressure from antiretroviral therapy (ART). Because many drug resistance mutations impair HIV fitness [6–10], replacement of TDR mutations with wild-type variants may confer a potential survival advantage. This is particularly true when resistant and wild-type viral populations co-exist, as typically occurs when resistance develops during treatment. However, when HIV is transmitted by a single drug-resistant virion, the emergence of wild-type variants requires evolution and back-mutation rather than emergence of an existing wild-type variant. Several studies have reported long-term persistence of most TDR mutations but have also documented replacement of certain mutations with wild-type variants [11–16]. Although valuable, these investigations did not have sufficient person-years of follow-up to quantify and compare replacement rates for each therapeutic drug class. Improved understanding of how quickly different mutation classes are replaced by wild-type variants is important for several reasons. First, most HIV diagnoses occur during chronic infection, rather than during acute and/or early infection. By the time genotyping is performed, TDR mutations may have waned below the detection threshold for population genotyping, but persist as minority variants. Therefore, knowledge about mutation replacement rates for each drug class could help clinicians interpret resistance tests performed during chronic infection. Second, the degree to which drug resistance will propagate among recently infected individuals depends on several factors including (1) the prevalence of drug resistance among chronically infected persons who are receiving partially suppressive therapy and (2) how long TDR persists in untreated persons and, thus, can propagate even without drug selection. The importance of propagation of transmitted mutations becomes amplified in resource-limited settings. Without genotyping and viral load monitoring, patients may initiate incompletely suppressive treatment regimens and sustain prolonged exposure to them. This leads to additional selection of drug resistance mutations [17, 18], further increasing the risk of resistance propagation and limiting patients’ second-line treatment options. Third, the interpretation of population-based surveys of TDR prevalence depends on understanding how long mutations persist after they are transmitted, because surveys will underestimate mutations that are quickly replaced by wild-type variants. To provide more detailed information about persistence of specific mutations, we analyzed participants in 2 large early infection cohorts with sustained periods of follow-up without treatment.

Prophylactic use of antimicrobial agents and microbicides has been proven for many infections, including surgical, gastrointestinal, upper respiratory, and meningococcal infections. Antiretroviral therapy for pregnant women prevents mother-to-child transmission of human immunodeficiency virus (HIV), which has become rare in settings where access to therapy is widespread. Postexposure prophylaxis after needlestick injury or significant sexual exposure is recommended on the basis of animal studies and case-control observational studies, although use of these interventions is limited to those who recognize exposure, have access, and have the power to use the interventions. Clinical trials are evaluating whether regular or preexposure use of antiretroviral therapy provides additional protection for persons at high risk of infection who are also offered standard prevention care, including HIV testing, counseling, condoms, and management of sexually transmitted infections. Trials are evaluating topical or oral use. Concerns have arisen with regard to optimal dosing strategies, costs, access, drug resistance, risk behavior, and the role of communities. Future implementation, if warranted, will be guided by the results of clinical trials in progress and engagement of communities exposed to HIV.

Coinfections with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are common globally. HIV infection modifies the course of HBV infection by increasing rates of chronicity, prolonging HBV viremia, and increasing liver-related morbidity. To minimize the emergence of HIV and/or HBV resistance, as well as the emergence of liver enzyme flares, the treatment of both infections should be coordinated. Lamivudine or emtricitabine monotherapy readily selects resistant strains in the YMDD motif of the polymerase gene. Adefovir monotherapy has moderate effectiveness in HIV-HBV‐coinfected patients who have YMDD mutation. If HBV treatment can be deferred until combination antiretroviral therapy for HIV infection is needed, the combination of tenofovir plus lamivudine or emtricitabine provides potent HBV therapy and a solid backbone for HIV combination antiretroviral therapy, and it likely decreases the emergence of HBV resistance.

Background. The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. Methods. HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. Results. Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. Conclusions. As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

(See the major article by Lehman et al on pages 1211–8.) The threat of drug resistance deserves careful attention from clinicians and public health officials advocating antiretroviral use as a way to control the human immunodeficiency virus (HIV) epidemic. Such antiretroviral use includes early treatment and preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP). Concerns about drug resistance were raised before rolling out widespread antiretroviral therapy in Africa, based on the assumption that adherence to therapy would be poor and drug resistance would become prevalent. Defying expectations, the benefits of antiretroviral therapy for improving health, averting death, and preventing transmission were subsequently proven to outweigh the risks of drug resistance, and adherence to therapy in African populations is often outstanding [1]. Fear of drug resistance is now raised as we consider rolling out PrEP. Daily oral PrEP using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or TDF alone is safe and effective for preventing HIV acquisition [2–5] in sexually active adults. Adherence is essential for effectiveness [2, 6, 7]. Such regimens do not fully suppress systemic HIV infection, so starting PrEP in people already infected with HIV may lead to drug resistance [2–4]. Recommendations for PrEP emphasize the importance of HIV testing prior to starting or restarting PrEP. In this issue of The Journal of Infectious Diseases, Lehman et al report new information about the risk of antiretroviral resistance from the Partners PrEP Study of men and women in Africa who are partnered with a person living with HIV [8]. (The usual term, “discordant couple,” obscures their commitment, courage, and cooperation.) The Partners PrEP Study is exceptional among randomized trials in that the levels of adherence were very high, with 71% of people randomly assigned to the active arm of the study having drug concentrations in plasma indicating consistent use [9]. Such higher adherence yielded higher PrEP effectiveness and makes this study ideal for evaluating the risk of drug resistance when PrEP fails to prevent HIV infection. The article confirms that drug resistance primarily occurs if systemic HIV infection is present when PrEP is started. This occurred in trials if people were enrolled during the HIV RNA–positive/HIV antibody–negative period of acute infection. Furthermore, drug resistance was primarily to FTC, which leaves multiple options for successful combination antiretroviral therapy. Importantly, the risk of drug resistance tended to be higher among people receiving FTC/TDF, compared with those receiving TDF alone (20% vs 5%; P = .1); this finding is consistent with nonhuman primate research on PrEP [10] and demonstrates how HIV develops resistance to the drug in the regimen with the lowest barrier to resistance. In HIV treatment, virological failure with resistance to only 1 drug in the multidrug regimen is the usual pattern, although resistance to other drugs appears later if a failing regimen is continued. This can occur with PrEP as well, as demonstrated by a trial participant who received FTC/TDF PrEP for 7 months before infection was detected by an oral fluid assay (seroconversion was detected after 1 month of PrEP, using a blood test conducted retrospectively) [4]. The lesson for PrEP drug development is that increasing the number of drugs in the regimen may increase, rather than decrease, the risk of drug resistance, especially if the added drug strongly selects for a single mutation having minimal effects on viral replication capacity. However, the risk of FTC resistance must be weighed with any added efficacy afforded by adding FTC to TDF for PrEP. In the Partners PrEP Study, the relative protection of receiving TDF alone vs FTC/TDF was 0.67 (95% confidence interval, .39–1.17) [11], a difference that would be clinically important and is consistent with findings from nonhuman primate studies. Additional evidence that TDF may fail more frequently when used without FTC is the higher rate of drug detection among TDF PrEP seroconverters (19 of 39 [49%]), compared with FTC/TDF PrEP seroconverters (7 of 25 [28%]). These rates of drug detection among heterosexual men and women seroconverting while receiving PrEP are higher than were observed among rectally exposed men who have sex with men and transgender women who seroconverted after receiving FTC/TDF PrEP (9%) [12], which helps explain why drug resistance during emergent infection while receiving PrEP was not observed in these groups [13]; rectally exposed people were not infected if substantial drug concentrations were present [14], leaving little opportunity for drug resistance to emerge. FTC may be particularly important for blocking infection after viral exposure to vaginal or penile tissues, because of its higher bioavailability and penetration beyond the intestinal tract compared with TDF [15]. Drug resistance due to PrEP in 5 persons in the Partners PrEP Study should be weighed against the prevention of an estimated 123 infections over the entire course of the study. As such, there were 25 HIV infections prevented for every drug-resistant infection caused. Such infections, had they occurred, could have caused secondary infections and substantial morbidity and mortality and would require lifelong therapy. Treatment of HIV infection has improved dramatically over the past 27 years, with increasingly safe and convenient regimens [16], although virological failure still occurs among 5%–24% of treated people per year [17]. The cumulative risk of drug resistance from PrEP services could be much lower than that associated with treating infections that would otherwise occur, as was predicted by mathematical models [18]: preventing HIV infection also prevents drug resistance. Other benefits of PrEP are important. Coupled with regular monitoring, PrEP affords detection of breakthrough HIV-1 infection in a few weeks to months after infection, while diagnosis is frequently delayed for years among people who are not receiving prevention services. Access to PrEP and PEP may motivate people recently or frequently exposed to HIV to seek services. As such, population engagement motivated by PrEP access also creates opportunities for earlier diagnosis and treatment, preventing transmission and disease while minimizing viral reservoir size and enabling more timely services for partners, which should include PEP, PrEP, and early treatment. Findings from trials may not necessarily apply to less controlled and monitored settings such as clinical practice. The Partners PrEP Study, like other trials, conducted monthly HIV testing, which minimized the duration of PrEP exposure after infection. Such frequent monitoring is not feasible in practice, and recommendations are to test for HIV every 3 months [19]. Nondaily use of PrEP or restarting PrEP after a lapse in use may occur in clinical practice, although this was not recommended in oral PrEP trials published so far. New information about the effectiveness and drug resistance risk associated with nondaily PrEP is expected from the ongoing ANRS-sponsored IPERGAY trial. Lehman et al also provide evidence that more-sensitive assays for HIV drug resistance are warranted. Standard genotypic and phenotypic assays miss low-frequency mutations within a viral population that may affect virological response to therapy. Deep sequencing can detect such variants, although the clinical utility of this technology awaits clearly defined cutoff frequencies for individual drug resistance mutations. Lehman et al report that viral mutations were associated with the treatment arms when they occurred in >1% of the virus population, providing additional support for this being a clinically significant cutoff associated with drug selection, rather than naturally occurring polymorphism. Treatment responses were not evaluated, although they are expected to be excellent if therapy is guided by resistance testing. There are ways to minimize the risk of drug resistance during PrEP use. Highly sensitive viral tests that detect RNA or antigen can rule out acute infection prior to starting PrEP. Point-of-care rapid RNA tests are available for research use, and feasible regulatory pathways leading to routine clinical use are urgently needed. If testing for HIV RNA or antigen is not available or not affordable, deferring PrEP in people with an acute viral syndrome will help, as the majority of acute HIV infections are symptomatic. Inviting PrEP users to inform providers about their stopping and starting of PrEP is important and provides an opportunity to arrange timely HIV testing. Home testing may make test access easier. Some practices used to minimize the risk of HIV resistance are ill advised: attempting to restrict access to PrEP is expected to foster intermittent dosing, hoarding of medications, sharing among friends and partners, and other unsupervised use. Fomenting fear of drug resistance is also misguided if it distracts us from fear of HIV itself, by far the greater threat to human health.

In a nonrandomized study of nonoccupational postexposure prophylaxis (PEP), a cross-sectional evaluation of subjects who were the source of human immunodeficiency (HIV) exposure was performed to characterize partners of index subjects seeking nonoccupational PEP against HIV. Among 401 index subjects, 64 (16%) recruited a source subject. Those in a steady relationship and those who knew that the source subject was HIV antibody positive were more likely to recruit their source subject. Source subjects reported high rates of past (78%) and current (69%) antiretroviral use; 46% of those using antiretroviral drugs had detectable plasma HIV-1 RNA levels. Antiretroviral resistance was detected in many source subjects who reported any use of antiretrovirals and was rare among source subjects who reported no history of antiretroviral use. Clinicians often make treatment decisions on the basis of incomplete knowledge of the source subject's HIV status or antiretroviral treatment history. The treatment history, particularly nonuse of a class of antiretroviral drugs, can be used to predict drug resistance.

An individual's sex influences plasma human immunodeficiency virus type 1 (HIV-1) RNA level and rate of CD4 cell decline, but the mechanism for this effect is currently unknown. To determine the effect of the ovulatory cycle on HIV-1 RNA level and lymphocyte subsets in HIV-infected women, blood specimens were obtained weekly from 14 women infected with HIV. Participants reported regular menses and were not using hormonal medications or narcotics. The occurrence of ovulation was verified by use of endocrine criteria. Ovulation occurred in 10 of the 14 women. Among women who ovulated, median HIV-1 RNA level fell by a median of 0.16 log10 from the early follicular phase to the midluteal phase (P=.03, Wilcoxon signed-rank test). When women who did not ovulate were included in the analysis, no significant fluctuation in plasma HIV RNA level was identified. Thus, the ovulatory cycle influenced circulating HIV-1 RNA levels, a finding that is plausible because of the known effect of sex hormones on lymphocyte function and cytokine production.

Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

We assessed the potential for international transmission of primary drug resistance among men who have sex with men newly diagnosed with human immunodeficiency virus (HIV) (n= 64) during the period in which they were unaware of their infection. During their exposure period, 55% of participants lived or traveled outside of the United States, and 59% had foreign-born sexual partners. Eighteen participants (28%) were classified as recently infected with HIV. Primary HIV-1 drug resistance was detected in eight participants (13%), four of whom were recently infected. Given the high frequency of international travel and prevalence of primary HIV-1 drug resistance among study participants, prevention strategies should incorporate specific counseling on risk of cross-border transmission.

To the Editor—We welcome with great interest a randomized controlled trial to evaluate the efficacy of doxycycline prophylaxis for sexually transmitted infections (STIs) as proposed by Boyd et al [1, 2], although we offer several concerns: Syphilis is readily treatable and curable; doxycycline prophylaxis, therefore, would be considered an alternative to guideline-recommended quarterly testing and treatment [3], which alone may be sufficient. Although we agree that a fully powered clinical trial would determine if a daily pill for prophylaxis could add value over quarterly testing and treatment, the resources might be better spent on improving compliance with existing recommendations for frequent testing. A clinical trial could evaluate whether STI prophylaxis would impair, or enhance, adherence to human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). This consideration would not apply to men who have sex with men (MSM) at high risk for certain STIs but at low risk for HIV (eg, MSM engaging only in condomless oral sex). Among MSM at high risk for HIV acquisition, pill-taking receptiveness might be best prioritized for HIV prevention efforts, as HIV remains without a cure and is responsible for worse outcomes; adherence to just 1 pill a day can prove challenging, as we observed in iPrEx. Alternatively, uptake of sexual health services may increase by offering a variety of prophylactic combinations, which might include HIV prophylaxis, STI prophylaxis, and contraception, depending on individual needs and desires. Importantly, offering doxycycline as prophylaxis will increase antibiotic pressure and may lead to increased drug resistance, especially within communities and sexual networks where multidrug-resistant bacterial infections, such as gonorrhea, have already emerged. Although doxycycline is typically well tolerated and there is extensive experience with its chronic use in acne or for long-term (including life-long) suppressive therapy, side effects such as sun sensitivity, esophagitis, and diarrhea are common. Despite these cautions, we agree that STI prophylaxis or a combined approach (ie, PrEP plus) would be worthwhile to examine in trials.

and industrious scholars, chiefly in Germany, undertook to show just how human the Bible was. They looked at statements which had previously been treated as items of historical fact and proceeded to prove that the biblical writers were not usually historians and that what they wrote was not usually history; they looked at various moral ideas, especially in the Old Testament, and showed that these ideas were not in harmony with the Sermon on the Mount or, for that matter, with the views of the Enlightenment or of the nineteenth century itself. In other words, the Bible was not an infallible guide either in matters of faith, where faith was related to history, or in matters of morals. The negative effect of this kind of criticism was so great that its positive results are often overlooked. On the