This article covers antiretroviral therapy, aims of treatment and when to start therapy, resistance, management of toxicities, adherence, and current and future treatment strategies
Mortimer Market Centre, Central and North West London NHS Foundation Trust, UK
Tristan Barber MD
Chelsea and Westminster Healthcare NHS Foundation Trust, London, UK
Email: [email protected]
The toxicity profiles of drugs have changed significantly in recent years and treatment strategies are constantly evolving with the emergence of new data. The role of using combination antiretroviral therapy (cART) as a strategy for prevention of onward transmission remains a contentious issue in patients with less advanced disease. Managing adherence to and tolerability of cART is key to successful treatment and pharmacists have a pivotal role in supporting these. The role of the introduction of generic medicines is also an important factor.
Introduction of ART
The introduction of ART was the most important advance in the management of HIV infection. Zidovudine, a nucleoside transcriptase inhibitor (NRTI) was the first approved therapy for HIV in 1987, having been originally developed as an anticancer agent.1 Further agents with similar actions were subsequently discovered, but in combination alone were not sufficient to fully suppress HIV. It was only when a new class of ART was developed, the protease inhibitors (PIs), that HIV management really took a leap forward. Although some ten years later, PIs were found to be highly effective at HIV suppression when used in combination with two NRTIs. A third class, non-nucleoside reverse transcriptase inhibitors (NNRTIs), although developed during this period as well, was incorporated with NRTIs after PIs. By the start of 1997, combination ART became the standard of care with declines in the rate of disease progression to AIDS and death.2 Since then, a further four classes have been discovered, allowing the flexibility for clinicians to choose regimens tailored to patients needs according to both personal, physical, psychological and lifestyle factors.
Aims of treatment and when to start
The aim of starting ART is to reduce the level of HIV in the blood, thereby allowing immune recovery and preventing HIV-related morbidity and mortality. Starting ART reduces the risk of progression to advanced HIV infection, or AIDS, as well as non-AIDS defining illnesses including cardiovascular, renal or hepatic disease.3 Furthermore, ART has now been shown to reduce the risk of onward sexual transmission, with compelling evidence provided by the HPTN 052 trial.4 While the evidence mainly relates to vaginal sex,4,5 it is likely the reduction in risk will also be seen for anal sex, currently the subject of ongoing trials.6
Current guidelines7 recommend ART should be started under the circumstances outlined below:
- CD4 <350 or <500 cells/mm3 for all patients
- AIDS defining illnesses WHO stage 3 or 4
- Regardless of the CD4 count with the following conditions:
(1) HIV-associated nephropathy
(2) Idiopathic thrombocytopenic purpura
(3) Neurocognitive impairment
- Depending on the CD4 count with the following conditions:
(2) Hepatitis B
(3) Hepatitis C
- Pregnancy and breastfeeding women
- HIV-positive individuals in serodiscordant partnerships
- Primary HIV infection
- Non-AIDS defining malignancies requiring immunosuppressive chemotherapy or radiotherapy.
Guidance does vary according to country and expert review and opinion on available and emerging data. The START trial which is currently ongoing, and reports in 2016, is designed to address the issue of whether ART should be started at CD4 counts >500.
There are currently 26 antiretroviral drugs approved by the Food and Drug Administration. These are categorised in six classes.
NRTIs are deoxynucleotide analogues, and inhibit the process of reverse transcription by competing with natural deoxynucleotides. This causes termination of the newly forming viral DNA chain. Drugs include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zalcitabine, zidovudine.
NNRTIs bind to, and alter, the reverse transcriptase enzyme. Drugs include delaviridine, efavirenz, etravirine, nevirapine and rilpivirine.
PIs prevent cleavage of the HIV structural proteins ‘gag’ and ‘pol’ which, in turn, prevents the formation of HIV into its mature infectious form. Drugs in this class include amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir and tipranavir.
Fusion inhibitors bind to the HIV transmembrane protein gp41, required for HIV entry into the CD4 cells. This action therefore prevents HIV from binding to and entering CD4 cells. The only drug in this class is enfuviritde, and is also the only subcutaneous drug currently available.
These bind to the chemokine receptor CCR5, which serves as a co-receptor for HIV entry into certain human cells. Binding to the CCR5 receptor effectively blocks the HIV transmembrane protein gp120 from access to the co-receptor, which in turn prevents the fusion process, which involves the HIV transmembrane protein gp41. The only drug available in this class is maraviroc.
Integrase inhibitors block the action of the integrase enzyme that normally inserts the DNA copy of the RNA HIV genome into the DNA of the host cell. Drugs include raltegravir, elvitegravir and dolutegravir.
Ritonavir and cobicistat can be considered as pharmacokinetic enhancers, which act as a boosting agent to raise drugs levels of the protease and integrase inhibitors. Both work by inhibiting cytochrome P450 enzymes that metabolise these classes. Higher drug levels can therefore be achieved at a lower dose of the second drug, consequently reducing side effects. Both also inhibit intestinal transport proteins, increasing overall absorption of several ART.
Key differences between these two enhancers include ritonavir alone having antiretroviral activity while cobicistat does not. Thusfar in clinical practice, cobicistat is only used with elvitegravir, while ritonavir with other protease inhibitors, but there are possibilities this may change as we acquire more evidence. While there is more experience with ritonavir, cobicistat is increasingly being considered as an alternative boosting agent, particularly where side effects are experienced with ritonavir.
When commencing ART in a patient who is treatment naive, a combination of three drugs should always be given. This enables effective maximal suppression of HIV, enabling sufficient drug pressure to suppress viral replication and preventing the development of drug resistance. Current guidelines vary in recommendations of what regimen should be started, but regimens should ultimately be determined in full discussion with patients and according to biological, psychological and social factors, as well as immunological and virological factors for some ART drugs.
Cost benefits and availability are also considered, particularly in the developing world setting but increasingly in the developed world setting too. Combination ART usually includes two NRTIs with one NNRTI, one ritonavir boosted protease inhibitor or one integrase inhibitor. The other classes are often reserved for when ART needs to be changed or there is failure with resistance. Treatment experienced patients require ART combinations constructed based on their previous ART history, as well as resistance profiles, and the usual factors as considered for naive patients.
Monotherapy and dual therapy are used under specific circumstances including tolerability, reduced pill burden and adherence, but cannot be considered as standard of care. Additional agents to the recommended standard triple ART regimens may be required if virological failure occurs with or without evidence of resistance, and is increasingly being used, albeit at physician’s discretion with no formal recommendations in guidelines, with primary HIV infection, very high viral loads, and in situations where there is a possible need for rapid viral load suppression (for example, occupational health). Four agents may be used in certain situations in pregnancy, where separate guidelines do exist.
ART side effects
Side effects are a concern for all patients starting any treatment. All ART drugs can cause unwanted side effects, but not everyone will experience them. Side effects cannot be categorised into inclusive categories, and can be asymptomatic and unpredictable. While some may resolve without any intervention, some can develop into life-threatening reactions. Prompt and regular review by a HIV physician is therefore paramount in managing and monitoring side effects, with blood or urine tests and occasionally imaging modalities. Side effects can broadly be considered as follows:
– Short-term: Starting soon after treatment (days to weeks), require simple measures to manage and then usually lessens or resolves fully. Such side effects include rashes, nausea, vomiting, diarrhea, headaches, mood changes, fatigue, and insomnia.
– Long-term: Starting later after treatment (months to years), may often be asymptomatic and usually requires a change in ART regime. Such side effects include lipodystrophy, kidney problems, liver problems, heart disease, metabolic changes, peripheral neuropathy, and bone problems.
– Likelihood: Very common, common, uncommon, rare, very rare or not known.
– Hypersensitivity (allergic) reactions: ART at greatest risk of hypersensitivity reactions include abacavir, nevirapine, (atazanavir, etravirine, efavirenz, darunavir, fosamprenavir, maraviroc and raltegravir). Abacavir hypersensitivity is associated with the presence of the HLA-B*5701 gene, which can be tested for with a blood test. The reaction can vary from a rash to fevers, shortness of breath, cough, sore throat, nausea, vomitting, diarrhoea, abdominal pain, tiredness, aches, generally feeling unwell. Nevirapine can result in mild to life-threatening liver toxicity, usually in the first four months. A very rare hypersensitity reaction called Steven Johnson syndrome can result after the administration of the other ART listed, as well as nevirapine. A rash with mucous membrane ulcers, skin blisters and facial swelling as well as systemic features including fever, muscle or joint aches, shortness of breath with systemic liver effects, can rapidly develop into a life-threatening reaction.
Side effects require prompt assessment and monitoring. A focused history and examination pertaining to the side effect should be taken, as well as a full drug history including prescribed, over-the-counter, herbal and recreational drugs, with exclusion of drug–drug interactions. Ensuring the ART is being taken as prescribed is also essential, including timing and whether taken with or without food. Depending on the severity of the side effect, both from a clinician and patient perspective, various measures can be instigated, as follows:
– Monitoring as an outpatient or inpatient.
– Symptomatic management, for example, anti-histamines, anti-emetics, loperamide, analgesia.
– Investigations, including blood and urine tests, imaging modalities.
– Alter timing.
– Alter food requirements.
– Stopping ART: Stopping ART containing an NNRTI, requires replacing all drugs in that combination with a protease inhibitor for four weeks, due to the long half-life and therefore potential for monotherapy with subsequent risk of drug resistance. Regimens containing protease inhibitors can be stopped simultaneously with no replacement.
– Switching ART: Various factors need to be considered as per starting ART, and whether a patient is treatment naive or experienced, as well as whether the HIV viral load is detectable or undetectable.
While there are 26 ART drugs available for treating HIV, there is still a need for new drugs to be developed for those unable to use existing products particularly due to drug resistance, but also due to tolerability for biological, psychological and social factors. New drugs are currently in development not only to increase the pool available within classes, but as novel strategies and administration routes.8 Clinical trials are currently in progress for two new NRTIs, tenofovir alafenamide fumarate which possibly has less renal and bone toxicitiy compared to tenofovir disoproxil fumarate, as well as lersivirine, a NNRTI and entry inhibitors cenicriviroc. More novel approaches include immune and gene therapy, which are being intensively researched but have been slow to develop due to complexities and potential risks. Results of long-acting ART including injectable rilpivirine and a new integrase inhibitor GSK744, which may provide easier administration routes for some and improve adherence to treatment, are eagerly anticipated with promising results to date. Occasionally newer drugs can be accessed prior to formal licencing via special application under certain circumstances, particularly in those patients with limited options for treatment, most often due to multidrug resistance.
Adherence to ART is essential for maintaining HIV suppression, and thereby reducing HIV and non-HIV related morbidity and mortality, reducing transmission, improving overall quality of life and prognosis. Poor adherence runs the risk the developing drug resistance, virological failure and loss of future treatment options. While many patients are able to maintain consistent levels of adherence, others are either non-adherent at the outset of starting ART or periodically non-adherent over their lifetime of taking ART. Engaging patients in treatment decisions at all times allows early identification of those at risk of adherence-related challenges, with continuous monitoring and support of paramount importance. Reasons for non-adherence can be complex, with perceptual or intentional barriers (for example, beliefs, emotions and preferences), practical or unintentional barriers (for example, limitations in capacity or resources).
Guidance on the assessment and support of adherence to medication exists in various models. It is important this is assessed at the outset and then at regular basis.
A continuum of interventions to support adherence is necessary to meet the needs of individual patients. Adherence support should adopt a multidisciplinary approach involving not only the physician, but nurses, pharmacists and social workers. Family and friends can be key motivators or help for some. There are many interventions available that can be applied prior to and if/when adherence issues arise. These need to be customised to the needs of individual patients, and are outlined as follows:
(1) Multidisciplinary approach.
(2) Evaluating knowledge about HIV and impact of ART.
(3) Identify and address medical barriers:
– Psychological factors including mental health history.
– Medication including prescribed, over-the-counter, herbal, recreational drugs.
(4) Identify and address psychological barriers:
– Beliefs, perceptions, non-disclosure and stigma.
(5) Identify and address social barriers:
– Social support, finances, housing, food security, lifestyle (work and social life), transport.
(6) Language and literacy.
(7) Review regimen including frequency, food requirements, storage, side effects, pill burden, pill size, pill formulation.
There are a number of interventions, some of which have been proven to be effective in improving adherence to ART, listed as follows:
– ART combination: Where there is a clinical concern of non-adherence, drugs of a higher genetic barrier to resistance are generally used in ART regimens.
– Dosing frequency: Once-daily dosing has been shown to improve non-adherence.9
– Fixed dose combinations or single tablet regimens: Current regimens include Atripla (tenofovir, emtricitabine, efavirenz), Eviplera (tenofovir, emtricitabine, rilpivirine), Stribild (tenofovir, emtricitabine, elvitegravir, cobicistat) and Triumeq (abacavir, lamivudine, dolutegravir). These support adherence, but the size of effect has yet to be determined with current available data.
Other practical measures include Dossette boxes or blister packs, written reminders as notes or on calendars, alarm reminders on watches or phones, or adherence applications on smartphones. Changing the formulation from tablets to liquids can help some, but limited availability can hinder constructing regimens solely based on liquids. Current drugs available as liquids are lopinavir, darunavir, ritonavir and zidovudine, while the combination pill of tenofovir and emtricitabine can be dissolved. In some extreme situations, the action of taking ART orally can serve as a complex psychological barrier to adherence and has been supported by the insertion of a percutaneous endoscopic gastrostomy.
- When commencing ART in a patient who is treatment-naïve, a combination of three drugs should always be given.
- Treatment-experienced patients require ART combinations constructed based on their previous ART history, as well as resistance profiles, and the usual factors as considered for naïve patients.
- Monotherapy and dual therapy are used under specific circumstances including tolerability, reduced pill burden and adherence, but cannot be considered as standard of care.
- All ART drugs can cause unwanted side effects, but not everyone will experience them.
- Side effects cannot be categorised into inclusive categories, and can be asymptomatic and unpredictable.
- Poor adherence runs the risk of developing drug resistance, virological failure and loss of future treatment options.
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- Fischl MAet al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med 1987;317:185–91.
- El-Sadr WM et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283–96.
- Cohen MS et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493–505.
- Donnell D et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet 2010;375: 2092–2098.
- Rodger A et al. HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER Study. 21st CROI, 3–6 March 2014, Boston. Oral late breaker abstract 153LB. www. croiwebcasts.org/console/player/22072
- Guidelines – DHHS: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents”. US Department of Health and Human Services. 2015-4-8; EACS: European AIDS Clinical Society (EACS). October 2013; WHO: WHO | Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection”. June 30, 2013. p. 38. ISBN 978 92 4 150572 7; British.
- AIDS Action Committee. New and experimental HIV drugs and treatments. www.aac.org/get-infohealth-library-topics/new-and-experimental-hiv. html#Anchor2.
- Haynes RB et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008;(2):CD000011.