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Clinical practice and challenges in HIV

Management of HIV patients has moved to a more comprehensive approach in which pharmacists can have a key role due to their knowledge, abilities and accessibility
Noe Garin PhD PharmD
Neus Pagès-Puigdemont PharmD
Mireia Riba PharmD
Nuria Fonts PharmD
Montserrat Masip PhD PharmD
Anna Feliu PhD PharmD
Pharmacy Department
Hospital de la Santa Creu i Sant Pau
Institut d’Investigacions Biomèdiques 
Sant Pau, Barcelona, Spain
The human immunodeficiency virus (HIV) remains a major public health challenge. At the end of 2014, 38.9 million people were living with HIV worldwide.1 In Europe, the burden of HIV affects three populations in particular: men who have sex with men (MSM); migrants from high-endemic areas; and African American communities.2 Other groups at risk 
are people who inject drugs, sex workers, prisoners and transgender individuals. 
Fortunately, the great effectiveness of highly active antiretroviral treatment (HAART) has led to a mortality decrease by 35% since 2005.1 In recent years, decreasing mortality, along with pill burden reduction and improved adverse effect profile has led to HIV being considered as a chronic condition. 
In this context, clinical care of people living with HIV should be tailored to each individual’s 
Aetiopathology, epidemiology and transmission
HIV is a lentivirus, a member of the Retroviridae family. Retroviruses are single-stranded RNA viruses that replicate by means of a characteristic intermediate form of double-stranded DNA. Reverse transcriptase is the enzyme responsible for this phase, which is extremely error-prone. As a consequence, a great number of mutations leading to drug resistance may occur. Virus mutations have constituted one of the greatest challenges of HIV treatment to date.
Sexual intercourse is the main mode of HIV transmission. There is a growing concern about this transmission route since the number of HIV diagnoses among MSM increased by 33% between 2004 and 2011 in Western and Central Europe.2 In contrast, HIV is prevalent in people who inject drugs in Eastern Europe and Central Asia. Thus, harm reduction policies including syringe exchange and safer sex programmes are required to prevent new infections in Europe. Infection through blood transfusions is very rare at present due to current rigorous testing. Finally, vertical transmission is possible but can be prevented in most cases with appropriate HIV treatment.
The early signs of HIV infection are mainly non-specific. During the first 3–6 weeks, an acute syndrome may appear, including pharyngitis, fever, arthralgia, nausea, etc. Regardless of this acute syndrome, if not treated, the infection course is mainly asymptomatic for a period of about ten years. In this asymptomatic phase, the virus infects specific cells in the organism, especially CD4 T lymphocytes. The reduction of CD4 T cells may expose the person to opportunistic infections, and eventually to the acquired immune deficiency syndrome (AIDS). AIDS is defined as a CD4 T cell count (CD4 count) below 200 cells/mm3 and/or the onset of specific diseases. 
Pneumocystis pneumonia, oesophageal candidiasis, encephalopathy, Kaposi sarcoma or wasting syndrome, among others, are typical conditions alerting to the presence of AIDS. Testing people at risk is a key challenge because infected, untreated, asymptomatic people are an increased HIV transmission risk to others along with the possibility of becoming the so-called ‘late presenters’, with advanced infection and severe health consequences.
Standard HAART regimens are drug combinations that target different stages of the HIV life cycle. The goals of antiretroviral therapy (ART) are to suppress viral replication and to preserve or restore the immune function. Current antiretrovirals effectively prevent HIV-related morbidity and mortality, which has contributed to the recent consideration of HIV infection as a manageable chronic disease.3,4
Moreover, HAART has also shown to be effective in preventing new infections, such as in the case of vertical and sexual transmission of HIV.3,4 There are six major classes of antiretroviral drugs used to treat HIV infection: nucleoside reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs); integrase strand transfer inhibitors (INSTIs); fusion inhibitors (FI); and CCR5 inhibitors. Drugs in these classes differ greatly in terms of safety, drug–drug interaction risk or place in therapy (Table 1).
Until very recently, guideline recommendations included the possibility of deferring treatment in those asymptomatic patients with a CD4 count above a specific threshold (for example: 500 cells/mm3) on the basis of the available evidence and the safety profile of antiretrovirals. However, new data supporting early initiation of ART have been published. The START study showed that immediate treatment in HIV-positive adults with a CD4 count above 500 cells/mm3 reduced both serious AIDS-related and serious non-AIDS-related events without increasing the rate of adverse effects.5
The TEMPRANO study found that immediate ART led to lower rates of severe illness compared with deferred ART, both overall and among patients with CD4 count above 500 cells/mm3.6 Additionally, the HPTN 052 study demonstrated that early starting of ART reduced rates of HIV-1 transmission to uninfected sexual partners and HIV-related clinical events.7 Considering these results, the European AIDS Clinical Society (EACS) and the World Health Organization (WHO) guidelines recommend the initiation of ART in HIV-positive individuals, regardless of their CD4 count.8,9
An individualised assessment should be made in order to determine the moment of ART initiation and the most suitable drugs for this regimen, balancing the advantages and drawbacks of each option. For example, when poor adherence to medication is expected, the initiation of therapy could be delayed in some cases. The initial ART regimen recommended by EACS consists of a combination of two NRTIs plus an INSTI, or an NNRTI or a boosted PI.8 These combinations achieve a viral load below 50 copies/mm3 in more than 75% of cases at 48 weeks with an acceptable tolerability. WHO guidelines recommend a combination of two NRTIs with an NNRTI as first-line ART9 (Table 2). Subsequent drug regimen changes due to virological failure are introduced according to the results of resistance testing. 
Clinical practice varies greatly across Europe. Differences on ART regimens from one country to another depend on various factors such as drug registration status, national policies, local availability, reimbursement and access to treatment. In some countries, there are national recommendations developed by HIV-AIDS associations or expert panels (for example, BHIVA in the UK or GESIDA in Spain). The EACS guidelines are intended to serve as a reference for these associations and the European countries without national guidelines.
Pharmaceutical care in people living with HIV
Pharmacists are important members of the HIV care team in helping patients get the most from their medication. A wide range of pharmacy services are known to be related to improved health outcomes.10
At the time of ART initiation, pharmacists verify the adequacy of the treatment: patient preferences, comorbidities, baseline viral load, CD4 count, drug resistance mutations and other concomitant medication. Pharmaceutical care also includes assessing patient willingness to initiate ART, identifying potential adherence barriers, providing patients with education about their illness and treatment, informing them about frequent adverse effects and their management, and evaluating potential drug interactions. 
Interactions between antiretrovirals and other drugs are relatively frequent. Drug interactions not only reduce the effectiveness and tolerability of the medication but may also lead to adverse effects. These interactions may involve pharmacokinetic changes at various levels (mainly metabolism) through multiple mechanisms. 
Valuable contributions of the pharmacist in relation to drug interactions include the evaluation of their clinical significance and the provision of management advice to both prescribers and patients. Useful resources to check HIV drug interactions are the product label information, HIV treatment guidelines,3,8,9 the University of Liverpool HIV Drug Interactions website11 and the drug information website from the Toronto General Hospital.12
Use of complementary and alternative medicines (CAM) is highly prevalent in HIV patients. Lifetime use of CAM has been described to range from 30 to 90%, with vitamins, herbs and supplements being the most commonly used.13,14 CAM are generally consumed to control disease-related symptoms, to manage adverse effects of HAART, to boost the immune system and to improve the general wellbeing. 
However, further research is needed to determine the efficacy and place in therapy of these treatments. In daily clinical practice, herbal therapies can have potential herb–drug interactions leading to increased adverse effects or decreased effectiveness of HAART.15 Pharmacists have a significant role in the identification and management of potential health risks related to the use of these therapies as part of the pharmaceutical care provision.
During follow-up visits, pharmacists assess medication adherence through motivational interviewing. These visits include monitoring of adverse effects, identification of medication errors, substance abuse, onset of mood disorders and other barriers that may impact negatively on drug compliance. Interventions such as the referral to mental health services or substance abuse programmes are occasionally needed to ensure the effectiveness of the treatment. 
Interventions aimed at improving adherence in HIV patients involve: continuing patient education, medication dispensing service in pill box organisers, reinforcement of linkage to care, use of medication reminders (mobile phone alarms, medical apps or calendars) and maintenance of patient motivation. Adverse effects are relatively frequent in patients on ART. Their management is critical, not only to maintain patients’ quality of life but also to prevent adherence problems. 
Pharmacists also play a key role in prevention. Interventions to improve adherence may result in a subsequent reduction of HIV viral load in infected patients. As aforementioned, it is known that low viral load levels are related to a significant decrease in risk of HIV transmission.1 Pharmacists have been involved in other prevention activities: support of local syringe exchange programmes; encouragement of safe sex practices; and identification of patients who need substance abuse treatment. Moreover, preconception counselling may be offered to women of child-bearing age who are considering getting pregnant. Adequate treatment for HIV has shown to be particularly effective in decreasing vertical transmission.1,3 Also, pharmacists should monitor for potential drug interactions in women taking hormonal contraceptives. 
In some regions, pharmacists are involved in HIV testing. Community pharmacies can be valuable HIV testing sites, especially for those patients with limited access to healthcare. Encouraging HIV testing is essential in high-risk populations as it is estimated that only 53% of people living with HIV know their status.1 Clinicians should provide counselling to people who undergo HIV testing in order to reduce HIV and other sexually transmitted diseases (STDs). Under these circumstances, pharmacists have to be familiar with and provide adequate information about pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). 
PrEP is the use of a specific ART before and during periods at high risk of acquiring HIV infection. The fixed-dose combination tablet of emtricitabine/tenofovir has proved to be effective in clinical trials as a useful tool for preventing new infections.8,9 Thus, PrEP has been implemented in some European countries. In people who might be good candidates for PrEP, it is important to emphasise that it does not provide protection against other STDs. Furthermore, PEP is defined as the use of antiretroviral drugs for four weeks after a potential HIV exposure. 
PEP should be started ideally within four hours after the exposure, and no later than 72 hours. Preferred PEP regimens are: emtricitabine/tenofovir qd (once a day) (alternative: zidovudine/lamivudine)+ raltegravir bid (twice a day), or + darunavir/ritonavir qd or + lopinavir/ritonavir bid. Emtricitabine/tenofovir + dolutegravir qd may be also considered as an alternative.8 For both PrEP and PEP, adherence to medication is crucial to maximise the benefits of antiretroviral drugs.
HIV continues to challenge health systems in Europe. The effectiveness and safety of HAART have helped to consider HIV as a chronic condition. This implies a need for further knowledge on long-term medication safety concerns and long-term impact of chronic HIV infection. 
Pharmacists have proved to play a key role in the care of people living with HIV, participating in a wide range of services such as the detection of interactions, adherence improvement, adverse-effects management and harm-reduction programmes. However, new treatments expected to appear in the near future and recent development of PrEP may result in a new clinical approach. Thus, continuing education is essential for pharmacists and other members of the healthcare team.
  1. World Health Organization. HIV/AIDS. Fact sheet no360. Updated November 2015. (Last accessed April 2016).
  2. Joint United Nations Programme on HIV/AIDS (UNAIDS). The Gap Report. 2014. UNAIDS. Geneva. (Last accessed April 2016).
  3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2016. (Last accessed April 2016).
  4. Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 2014;384(9939):258–71.
  5. Lundgren JD et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015;373(9):795–807.
  6. Danel C et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med 2015;373(9):808–22.
  7. Cohen MS et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365(6):493–505.
  8. European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV-infected adults. Version 8. October 2015. English version. (Last accessed April 2016).
  9. World Health Organization. Policy brief: consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: what’s new. November 2015.… (accessed March 2016).
  10. Schafer JJ et al. Guidelines on pharmacist involvement in HIV care. Medication therapy and patient care: Specific practice areas – Guidelines. American Society of Hospital Pharmacy. 2015.… (Last accessed April 2016).
  11. Liverpool HIV Pharmacology Group (LHPG). HIV drug interactions webpage. 2016. (Last accessed April 2016).
  12. Immunodeficiency Clinic. Toronto General Hospital. University Health Network. Drug Information for Healthcare Professionals. 2016. (Last accessed April 2016).
  13. Lorenc A, Robinson N. A review of the use of complementary and alternative medicine and HIV: issues for patient care. AIDS Patient Care STDS 2013;27(9):503–10.
  14. Canadian AIDS Treatment Information Exchange (CATIE). A practical guide to herbal therapies for people living with HIV. Toronto, Canada. 2008. (Last accessed April 2016).
  15. Moltó J et al. Use of herbal remedies among HIV-infected patients: patterns and correlates. Med Clínica 2012;138(3):93–8.