Although the balance of recent evidence supports the efficacy of antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) against HIV-1 infection, recent negative trial results are perplexing. Of seven trials with available HIV endpoints, three different products have been tested: tenofovir 1% vaginal gel, oral tenofovir disoproxil fumarate (TDF) tablets, and TDF/emtricitabine tablets. Six of these trials were conducted exclusively in sub-Saharan Africa; all found the products to be well tolerated, and four demonstrated effectiveness. Furthermore, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission to HIV-negative partners in HIV-serodiscordant couples. These results, along with human and animal data, provide substantial evidence for the efficacy of antiretroviral-based HIV prevention. Yet assessment of oral TDF/emtricitabine in the FEM-PrEP study and of oral and vaginal tenofovir in the Microbicide Trial Network (MTN)-003 trial (VOICE) was stopped for futility. How do we make sense of these discrepant results? We believe that adherence is a key factor, although it cannot be the only factor. Expanding upon a recent editorial in the Lancet, we discuss the impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection.

Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention.

Ethinyl Estradiol and 17β-estradiol in Combined Oral Contraceptives: Pharmacokinetics, Pharmacodynamics and Risk Assessment

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1469-0691.12690

New epidemiology of Staphylococcus aureus infection in Africa

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.

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Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

The integration of human immunodeficiency virus (HIV) care and family planning services is critical for more than 17.4 million HIV-infected women, of whom nearly 95% live in low- and middle-income countries (LMICs) [1, 2]. These women face an increased risk for complications following an unplanned pregnancy, including the risk of vertical transmission of HIV [3, 4]. Accordingly, the World Health Organization (WHO) recommends the use of long-acting, reversible contraceptive methods for family planning, including progestin-releasing subdermal implants [5], and the use of efavirenz-based antiretroviral therapy (ART) as preferred first-line treatment for HIV-1 [6, 7]. Nevirapine-based ART remains an alternative; however, its use is declining due to inferior virologic efficacy and a higher rate of toxicity compared with efavirenz [6, 8]. Despite the benefits of both implantable contraceptives and ART, drug–drug interactions between these recommended therapies represent a critical barrier to effective family planning methods for HIV-infected women.

The levonorgestrel-releasing subdermal implant is widely used in sub-Saharan Africa [9]. After insertion, the implant may remain in place for up to 5 years, with a low failure rate of 0.1 pregnancy per 100 woman-years during the first year [10]. Levonorgestrel is released from the implant initially at 100 μg/day, decreasing to 40 μg/day within 1 year and to 30 μg/day within 3 years, providing stable daily drug concentrations [10]. Levonorgestrel is metabolized via hepatic enzymes, and coadministration of medications that induce or inhibit the cytochrome P450 (CYP) enzyme system influences levonorgestrel exposure [10]. The risk for drug–drug interaction compromising contraception efficacy is greatest with antiretrovirals that induce CYP3A4, including efavirenz and nevirapine. Few data characterize the impact of the drug–drug interaction between ART and levonorgestrel. However, when oral levonorgestrel for emergency contraception was combined with efavirenz, levonorgestrel exposure decreased 56%, as measured by the area under the concentration time curve (AUC) in 12 healthy volunteers [11]. In contrast, 3 HIV-infected women who received nevirapine-based ART and oral contraceptive pills had higher levonorgestrel exposure compared with 3 HIV-infected participants who did not receive ART (AUC0–24 hours 147 vs 114 ng h/mL) [12]. Further, a retrospective analysis among 570 HIV-infected women who used the levonorgestrel-releasing implant identified concomitant use of efavirenz as the only factor correlated with unintended pregnancy (15 of 16 observed pregnancies occurred in women receiving efavirenz; 12.4% pregnancy rate); no pregnancies occurred among 208 women who received nevirapine [13]. There is no known interaction between nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and levonorgestrel [14]. No evidence exists regarding the pharmacokinetic effect of ART on levonorgestrel-releasing implants.

Noting the absence of high-quality studies, recent WHO guidance states that women on efavirenz- or nevirapine-based ART can “generally use” subdermal implants, because the benefits of contraception generally outweigh the risks [5, 15]. Our primary objective in this study was to assess the effect of efavirenz- or nevirapine-based ART on the pharmacokinetic exposure of levonorgestrel released from a subdermal implant in HIV-infected women over 24 weeks. We hypothesized that levonorgestrel concentrations would be reduced but would remain effective. Secondary objectives were to assess levonorgestrel, efavirenz, and nevirapine concentrations; HIV-related outcomes; pregnancies; and levonorgestrel-related adverse events, each over 48 weeks.

/pdf/unintended-pregnancies-observed-with-combined-use-of-the-3a546adxql.pdf

Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks

Life-threatening infections present major challenges for health systems in Malawi and the developing world because routine microbiologic culture and sensitivity testing are not performed due to lack of capacity. Use of empirical antimicrobial therapy without regular microbiologic surveillance is unable to provide adequate treatment in the face of emerging antimicrobial resistance. This study was conducted to determine antimicrobial susceptibility patterns in order to inform treatment choices and generate hospital-wide baseline data. Culture and susceptibility testing was performed on various specimens from patients presenting with possible infectious diseases at Kamuzu Central Hospital, Lilongwe, Malawi. Between July 2006 and December 2007 3104 specimens from 2458 patients were evaluated, with 60.1% from the adult medical service. Common presentations were sepsis, meningitis, pneumonia and abscess. An etiologic agent was detected in 13% of patients. The most common organisms detected from blood cultures were Staphylococcus aureus, Escherichia
coli, Salmonella species and Streptococcus pneumoniae, whereas Streptococcus pneumoniae and Cryptococcus neoformans were most frequently detected from cerebrospinal fluid. Haemophilus influenzae was rarely isolated. Resistance to commonly used antibiotics was observed in up to 80% of the isolates while antibiotics that were not commonly in use maintained susceptibility. There is widespread resistance to almost all of the antibiotics that are empirically used in Malawi. Antibiotics that have not been widely introduced in Malawi show better laboratory performance. Choices for empirical therapy in Malawi should be revised accordingly. A microbiologic surveillance system should be established and prudent use of antimicrobials promoted to improve patient care.

https://cdr.lib.unc.edu/downloads/gx41mk85t

Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance

This letter to the editor addresses the concern regarding women who are HIV positive and interested in oral contraceptives. HIV positive women are typically advised to avoid using combined oral contraceptives which proves difficult because COC’s are the most widely circulated contraceptives in the world. Health care professionals must understand the pharmacokinetics and pharmacodynamics between COC pills and ART treatments. This is especially important in areas with high rates of HIV positive women or where rates exceed 10% HIV positive females within the HIV population. In these areas women should be informed of the most effective treatment for their unique condition.

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Combined oral contraceptives and antiretroviral PK/PD in Malawian women: pharmacokinetics and pharmacodynamics of a combined oral contraceptive and a generic combined formulation antiretroviral in Malawi.

Gabriel Malunga

Papers

Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance

Combined oral contraceptives and antiretroviral PK/PD in Malawian women: pharmacokinetics and pharmacodynamics of a combined oral contraceptive and a generic combined formulation antiretroviral in Malawi.