Genetic Diversity in Drug Transporters: Impact in African Populations.

Polymorphisms in drug transporters, like the adenosine triposphate-binding cassette (ABC) and solute carrier (SLC) superfamilies, may contribute to the observed diversity in drug response in African patients. This review aims to provide a comprehensive summary and analysis of the frequencies and distributions in African populations of ABC and SLC variants that affect drug pharmacokinetics (PK) and pharmacodynamics (PD). Of polymorphisms evaluated in African populations, SLCO1B1 rs4149056 and SLC22A6 rs1158626 were found at markedly higher frequencies than in non-African populations. SLCO1B1 rs4149056 was associated with reduction in rifampin exposure, which has implications for dosing this important anti-tuberculosis therapy. SLC22A6 rs1158626 was associated with increased affinity for antiretroviral drugs. Genetic diversity in SLC and ABC transporters in African populations has implications for conventional therapies, notably in tuberculosis and HIV. More PK and PD data in African populations are needed to assess potential for a different response to drugs compared with other global populations.

Managing Pharmacotherapy in People Living With HIV and Concomitant Malignancy.

Objective: To describe data with selected malignancies in people living with HIV (PLWH) and HIV in individuals affected by both conditions and to summarize drug-drug interactions (DDIs) with clinical recommendations for point-of-care review of combination therapies. Data Sources: Literature searches were performed (2005 to December 2018) in MEDLINE and EMBASE to identify studies of malignancies in PLWH in the modern era. Study Selection and Data Extraction: Article bibliographies and drug interaction databases were reviewed. Search terms included HIV, antiretroviral therapy, antineoplastic agents, malignancies, and drug interactions. Data Synthesis: In the pre-antiretroviral therapy (ART) era, malignancies in PLWH were AIDS-defining illnesses, and life expectancy was shorter. Nowadays, PLWH are living longer and developing malignancies, including lung, anal, and prostate cancers. Concurrently, the oncology landscape has evolved, with novel oral targeted agents and immunotherapies becoming routine elements of care. The increased need for and complexity with antineoplastics in PLWH has led to recommendations for multidisciplinary care of this unique population. Evaluation of DDIs requires review of metabolic pathways, absorption mechanisms, and various drug transporters associated with antineoplastics and ART. Relevance to Patient Care and Clinical Practice: This review summarizes available data of non-AIDS-defining malignancies, principles of HIV care in the patient with malignancy, and guidance for assessing DDIs between antineoplastics and ART. Summary DDI tables provide point-of-care recommendations. Conclusions: The availability of ART has transformed AIDS into a chronic medical condition, and PLWH are experiencing age-related malignancies. Pharmacists play an important role in the management of this patient population.

Addressing the intersection between alcohol consumption and antiretroviral treatment: needs assessment and design of interventions for primary healthcare workers, the Western Cape, South Africa.

BACKGROUND: At the points where an infectious disease and risk factors for poor health intersect, while health problems may be compounded, there is also an opportunity to provide health services. Where human immunodeficiency virus (HIV) infection and alcohol consumption intersect include infection with HIV, onward transmission of HIV, impact on HIV and acquired immunodeficiency syndrome (AIDS) disease progression, and premature death. The levels of knowledge and attitudes relating to the health and treatment outcomes of HIV and AIDS and the concurrent consumption of alcohol need to be determined. This study aimed to ascertain the knowledge, attitudes and practices of primary healthcare workers concerning the concurrent consumption of alcohol of clinic attendees who are prescribed antiretroviral drugs. An assessment of the exchange of information on the subject between clinic attendees and primary healthcare providers forms an important aspect of the research. A further objective of this study is an assessment of the level of alcohol consumption of people living with HIV and AIDS attending public health facilities in the Western Cape Province in South Africa, to which end, the study reviewed health workers' perceptions of the problem's extent. A final objective is to contribute to the development of evidence-based guidelines for AIDS patients who consume alcohol when on ARVs. The overall study purpose is to optimise antiretroviral health outcomes for all people living with HIV and AIDS, but with specific reference to the clinic attendees studied in this research. METHODS: Overall the research study utilised mixed methods. Three group-specific questionnaires were administered between September 2013 and May 2014. The resulting qualitative data presented here supplements the results of the quantitative data questionnaires for HIV and AIDS clinic attendees, which have been analysed and written up separately. This arm of the research study comprised two, separate, semi-structured sets of interviews: one face-to-face with healthcare workers at the same primary healthcare clinics from which the clinic attendees were sampled, and the other with administrators from the local government health service via email. The qualitative analysis from the primary healthcare worker interviews has been analysed using thematic content analysis. RESULTS: The key capacity gaps for nurses include the definition of different patterns and volumes of alcohol consumption, resultant health outcomes and how to answer patient questions on alcohol consumption while on antiretroviral treatment. Not only did the counsellors lack knowledge regarding alcohol abuse and its treatment, but they were also they were unclear on their role and rights in relation to their patients. Doctors highlighted the need for additional training for clinicians in diagnosing alcohol use disorders and information on the pharmacological interventions to treat alcoholism. CONCLUSION: Pertinent knowledge regarding patient alcohol consumption while taking ARVs needs to be disseminated to primary healthcare workers.

Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus.

BACKGROUND: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions. METHODS: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil. RESULTS: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 ± 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response. CONCLUSION: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions.

Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial.

OBJECTIVES: Maximizing ART efficiency is of growing interest. This study assessed the efficacy, safety, pharmacokinetics and economics of a darunavir dose-reduction strategy. METHODS: This was a multicentre, randomized, open-label clinical trial in HIV-infected patients with plasma HIV-1 RNA <50 copies/mL while receiving triple ART including 800 mg of darunavir once daily. Participants were randomized to continue 800 mg of darunavir (DRV800) or to 600 mg of darunavir (DRV600), both once daily. Treatment failure was defined as two consecutive HIV-1 RNA determinations >50 copies/mL or discontinuation of study treatment by week 48. The study was registered at https://www.clinicaltrialsregister.eu (trial number 2011-006272-39). RESULTS: Fifty participants were allocated to each arm. The mean (SD) CD4+ T cell count at baseline was 562 (303) cells/mm(3) and HIV-1 RNA had been <50 copies/mL for a median (IQR) of 106.9 (43.4-227.9) weeks before enrolment. At week 48 no treatment failure had occurred in 45/50 (90%) DRV600 patients and in 47/50 (94%) DRV800 patients (difference -4%; 95% CI lower limit, -12.9%). When only patients with virological data were considered, that endpoint was met by 45/48 (94%) in the DRV600 arm and 47/49 (96%) in the DRV800 arm (difference -2.2%; 95% CI lower limit, -9.6%). Darunavir exposure was similar in the two arms. The average reduction in annual cost per successfully treated DRV600-arm patient was US$7273. CONCLUSIONS: The efficacy of a darunavir daily dose of 600 mg seemed to be similar to the efficacy of the standard 800 mg dose in virologically suppressed HIV-infected patients on triple ART. This strategy can potentially translate to substantial savings in the cost of care of HIV-infected patients.

Generic antiretroviral drugs in developing countries: friends or foes?

Although second-line generic antiretroviral drugs are of great value in developing countries, there are concerns regarding their quality. We studied a generic Lopinavir/ritonavir (200/50  mg; Arga-L, India) marketed in the Republic of Congo but not prequalified by WHO. Despite adequate quantitative and qualitative drug content, Arga-L had a bio-availablility of 10% compared with Kaletra. To avoid selection of drug-resistant HIV, rigorous pharmacological monitoring of generic drugs not prequalified by WHO must be a priority.

What do we know about antiretroviral treatment of HIV in women?

As the number of women living with HIV continues to increase, the lack of sex-specific data on responses to antiretroviral therapy (ART) becomes increasingly problematic. Establishing the specific needs of women has been hampered by a strong male bias of study populations in clinical trials resulting in a lack of female-specific data for ART. The limited data currently available make it difficult to draw conclusions about the pharmacokinetic profile and clinical efficacy of ART in women. Data relating to the safety and tolerability profiles of ART in women are more plentiful, with indications that women may experience adverse event profiles distinct from those experienced by men. This, in turn, may be a factor in the generally higher rates of discontinuation of ART observed in women. Psychological and social aspects of HIV infection are particularly pertinent for women and girls, presenting potential barriers to diagnosis, access and adherence to therapy. Understanding these factors, in conjunction with an increase in clinical trial and real-world data specific to women with HIV is required to provide clearer guidance on optimum ART options for women.

Generic and branded drugs for the treatment of people living with HIV/AIDS.

HIV/AIDS care has benefited tremendously from the availability of antiretroviral (ARV) drugs, both branded and generic. Drug discovery and innovation is the result of direct investment in the development of branded medications, a crucial process for future improvements in care. However, the cost of branded medications is too high for resource-limited countries, where most persons with HIV/AIDS live. Generic drugs dramatically lower the cost of care; however, their safety and efficacy must be ensured and maintained. Proven bioavailability and bioequivalence, in addition to satisfactory manufacturing, distribution, and administration, are keys to successfully implementing the use of qualified generic ARVs. Agencies such as the US Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the World Health Organization (WHO), continue to strengthen the surveillance process through which qualified generic and branded drugs are provided worldwide. Generic drugs have the potential to cause harm if rigorous standards for their use are not followed, but those that are qualified offer great promise in the treatment of HIV/AIDS.