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CP, Oct, p393-99, CF2 24/9/09 11:58 Page 393 Vol 1 October 2009 Clinical Pharmacist HIV infection combination antiretroviral therapy By Rosy Weston, MRPharmS, and Brett Marett, DipClinPharm, MRPharmS he treatment of HIV is currently focused on drug intervention with antiretrovirals (ARVs). There is no known cure for HIV or a preventive vaccine. Combination ARV therapy (CART) is the use of at least three ARVs in combination to treat individuals infected with HIV, with the aim of prolonging life and improving its quality. According to the Health Protection Agency, 70% of diagnosed HIV-positive people in the UK are currently receiving CART. Treatment objectives are to suppress viral replication to a viral load (VL) below the level of detection (currently <50 copies/ml); increase the number of CD4 cells; and preserve the function of the immune system. A patient’s CD4 count is used as a surrogate marker of immune system functioning, and CART aims to improve or preserve this count and maintain viral suppression for as long as possible. Treatment of HIV is lifelong and adherence to CART is essential. Recent developments in CART have centred on improving tolerability, reducing long-term side effects and providing convenience in administration. Early detection of HIV and drug treatment with effective ARVs is crucial to successful management of the patient. This article will focus on CART, treatment monitoring and future strategies in adults. T SUMMARY The diagnosed HIV population in the UK is living longer, developing significant comorbidities and accessing more healthcare services. Combination antiretroviral therapy (CART) is the cornerstone of HIV treatment and is essential to prevent disease progression and the development of opportunistic infections. Surrogate markers are used to monitor response to CART, along with clinical symptoms and side effects. CART changes are often needed to avoid toxicity and to overcome virological and immunological failure. Treatment-experienced patients have complex treatment needs and should be managed with expert advice. Management of drug interactions is critical to ensure adequate drug levels and avoidance of drug toxicity. Future strategies are focusing on reducing treatment toxicity, HIV prevention and other immune therapies. This guidance is based on current evidence and expert opinion. What to start with Currently there are 22 ARVs licensed for the treatment of HIV (see Box 2, p394). Treatment selection is dependent on patient-specific factors, such as presence of hepatitis, tuberculosis, cardiovascular risk factors, neurocognitive impairment and other comorbidities. It is also important to consider patient preference for individual medicines or formulations and concerns around potential toxicities. Some patients may have transmitted or primary resistance, which means that the virus has genetic mutations When to start Historically the question of when to start anti-HIV treatment has been dictated by the toxicity and tolerability of ARVs and the ability of individual patients to adhere to regimens. Early CART regimens involved multiple daily doses and high pill burden. The development of less toxic medicines and new ways of using older treatments has helped reduce both dosing frequency and pill burden with improved patient tolerability. With CART now being better tolerated and more convenient to take, the debate concerning the best time to start therapy has begun. Data from several large cohort studies suggest that treating patients earlier in the course of their infection (CD4 cell counts >350 cells/µl) can delay the development of AIDS-related infections and reduce morbidity and mortality from conditions that have not traditionally been associated with HIV.1,2 A large multinational randomised controlled trial aims to address the important question of when to start CART.3 The British HIV Association (BHIVA) adult treatment guidelines recommend when to start treatment (see Box 1). Box 1: BHIVA guidance on when to start CART4 PRESENTATION RECOMMENDATIONS Primary infection OR neurological involvement OR CD4 count <200 cells/μl for more than three months OR AIDS-defining illness Treat in clinical trial Established infection CD4 <200 cells/μl CD4 201–350 cells/μl CD4 351–500 cells/μl CD4 >500 cells/μl Treat Treat as soon as possible when patient ready Treat in specific situations* Consider enrolment in “when to start trial” AIDS diagnosis Treat * HIV-related comorbidities; consider treatment where treatment is indicated for hepatitis B also; patients with established cardiovascular disease or a very high risk of cardiovascular events may consider treatment CLINICAL FOCUS Since the advent of combination antiretroviral therapy in the mid-1990s HIV-infected individuals are now living longer with improved quality of life. Medication adherence is vital for successful treatment 393 CP, Oct, p393-99, CF2 CLINICAL FOCUS 394 24/9/09 Clinical Pharmacist 11:58 October 2009 Page 394 Vol 1 associated with ARV resistance despite the patient not having being exposed to any ARVs. The prevalence of drug resistance in treatment-naive patients in the UK is around 8%. BHIVA guidelines recommend that a resistance test should be undertaken for all newly diagnosed patients, because the presence of mutations associated with drug resistance can have an impact on CART selection. BHIVA guidelines also recommend which ARVs to consider first line for treatment-naive patients (Box 3). Mechanisms of action ARVs can be divided into five main classes depending on where they act in the replication cycle (see Box 4 and p388 of accompanying article). ❝ HIGH LEVELS OF ADHERENCE TO ANTIRETROVIRAL THERAPY ARE CRITICAL ❞ Effective CART in treatment-naive patients should achieve viral suppression with an undetectable VL within 12 to 24 weeks of starting therapy. If the VL decline is slow, then the individual’s adherence should be checked Box 2: ARVs available in the UK (by class) NNRTI PROTEASE INHIBITOR ENTRY/FUSION INHIBITOR Abacavir*† Didanosine Emtricitabine‡§ Lamivudine*†|| Stavudine Tenofovir‡§ Zidovudine†|| Efavirenz§ Etravirine Nevirapine (Rilpivirine)º (Lersivirine)º Atazanavir Enfuvirtide Darunavir Maraviroc Fosamprenavir Indinavir Lopinavir¶ Nelfinavir Ritonavir¶ Saquinavir Tipranavir Adherence and treatment support High levels of adherence to antiretroviral therapy are critical to achieving treatment success. The reasons why patients find taking anti-HIV medicines difficult are many and some examples include: ● ● ● ● ● ● ● ● Monitoring response to treatment NRTI along with other potential reasons for poor response, such as drug-drug interactions or presence of resistance. Patients are described as being on stable antiretroviral therapy when the VL remains below 50 copies/ml with a sustained CD4 cell response. INTEGRASE INHIBITOR Raltegravir (Elvitegravir)º * Co-formulated as Kivexa NRTI = Nucleoside/tide reverse transcriptase inhibitor † Co-formulated as Trizivir NNRTI = Non-nucleoside reverse transcriptase inhibitor ‡ Co-formulated as Truvada § Co-formulated as Atripla || Co-formulated as Combivir ¶ Co-formulated as Kaletra º Unlicensed medicines undergoing late-stage clinical investigation (shown in brackets) Failure to acknowledge that they need treatment Not understanding the benefits of treatment Perceived harm from taking antiretrovirals Fear of developing stigmatising side effects Intolerance to side effects Misunderstanding how to take CART Forgetting to take CART Fear of disclosure of HIV status Box 4: Mechanisms of action Entry inhibitors ● Bind to chemokine receptors (X4/R5) Fusion inhibitors ● Block the viral surface protein gp41 Reverse transcriptase inhibitors ● Three types — nucleosides, SUMMARY NRTI NNRTI BHIVA 2008 preferred Two NRTIs + efavirenz Tenofovir + Efavirenz emtricitabine PROTEASE INHIBITOR (PI) OR Abacavir + lamivudine BHIVA 2008 alternative Two NRTIs + ritonavirboosted PI Didanosine + lamivudine Lopinavir/ritonavir* OR Fosamprenavir/ ritonavir* OR Didanosine + emtricitabine OR OR Atazanavir/ritonavir* Zidovudine + lamivudine Saquinavir/ritonavir* Specific groups OR Nevirapine† Atazanavir‡ * Boosting dose of ritonavir † Only when CD4 cell count <250 cells/μl (women) or <400 cells/μl (men) ‡ When cardiovascular disease established and a PI is required NRTI = Nucleoside/tide reverse transcriptase inhibitor NNRTI = Non-nucleoside reverse transcriptase inhibitor preventing the conformational change necessary to allow fusion of viral and cell membranes nucleotides and non-nucleosides ● Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) act on the viral reverse transcriptase enzyme, which converts viral RNA into DNA. They work by terminating the DNA chain ● Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind tightly to and block reverse transcriptase Box 3: BHIVA guidance on what CART to start4 GUIDELINE on host cells, blocking their use as a co-receptor for HIV cell entry ● A proprietary assay (Trofile) is used to determine the viral tropism, which is the type of chemokine receptor the virus uses — either X4, R5 or both ● Trofile guides use of X4 or R5 entry inhibitor — currently only an R5 inhibitor is licensed (maraviroc) Integrase inhibitors ● Block the integrase enzyme, which Protease inhibitors ● Bind to the viral protease enzyme incorporates viral DNA into the host cell DNA blocking cleavage of the viral amino acid chain to its constituent proteins ● Almost always used in conjunction with a small dose of ritonavir which inhibits the metabolism of PIs. This results in higher PI levels, improving potency and permitting more flexible dosing. This practice is known as “boosting” CP, Oct, p393-99, CF2 Clinical Pharmacist 11:58 October 2009 Page 396 Vol 1 HIV drug resistance can develop rapidly if drugs are taken late, missed or stopped suddenly. The latter is especially important for drug combinations containing medicines with both long and short half-lives. Levels of ARVs with longer half-lives can remain within the body, whereas those with short half-lives decline rapidly after stopping treatment. In some situations this can result in monotherapy — which can lead to the development of resistance. Since drug therapy is a life-long commitment, adherence support and medication counselling are fundamental to ensure successful patient outcomes. Francis Sheehan | SPL CLINICAL FOCUS 396 24/9/09 Toxicity Patients may experience toxicity to CART either early in treatment or longer-term. These toxicities can range from barely noticeable to distressing with considerable impact on the patient’s quality of life. Common side effects are listed in Box 5. A metabolic syndrome — involving dyslipidaemia, body shape changes and diabetes — is often described as a long-term toxicity. Pharmaceutical intervention with lipidlowering drugs and antidiabetic medicines, along with lifestyle changes (cessation of smoking and suitable diet and exercise) are important to improve patient outcomes. Pill burden Box 5: Examples of ARV side effects Side effects associated with initial therapy ● Nausea and vomiting ● Diarrhoea ● Headache ● Abdominal bloating and flatulence ● Mild-to-moderate rash, rarely Stevens-Johnson syndrome ● Abnormal liver function tests and hepatotoxicity Side effects associated with long-term therapy ● Changes in renal function ● Changes in bone mineral density ● Dyslipidaemia ● Diabetes and changes in glucose control ● Peripheral neuropathy ● Lipodystrophy and changes in body shape Box 6: CART change after first virological failure4 INITIAL REGIMEN 2 × NRTI + 1 × PI OPTIONS TO CONSIDER 2 × NRTI*† + 1 × NNRTI OR 2 × NRTI* + 1 × boosted PI Treatment changes and failure Individuals on treatment may need to change therapy due to the development or persistence of side effects, or because of virological or immunological failure (see below). Patients who experience initial side effects that are unable to be alleviated by medicines for symptom control may be forced to change one or more of the ARVs. As discussed previously some patients who have been on treatment for many years will develop long-term toxicity to medicines and also need treatment modification. Virological failure Virological failure is when the VL is not suppressed by CART to <50 copies/ml or when there is a sustained VL rebound. Each of these can be associated with poor adherence, baseline resistance to ARV, inadequate drug levels, or lack of CART potency. BHIVA recommends that patients who fail virologically for the first time should have a resistance test performed and their ARVs switched (see Box 6). Immunological failure Immunological failure is when the patient’s immune system fails to respond to treatment; CD4 cell counts may not improve despite the VL being undetectable. Such patients can be difficult to treat, but some ARV switches may increase the individual’s CD4 count. Because the CD4 count is only a surrogate marker, it is important to monitor these patients closely for any symptoms of disease progression. OR 2 × NRTI + 1 × NNRTI 3 × NRTI 1 × NNRTI + 1 × boosted PI‡ + 1–2 × NRTI* Treatment-experienced patients 2 × NRTI* + 1 × boosted PI A small proportion of individuals in the UK are heavily treatment-experienced. In such patients the virus has developed resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). ARV resistance evolves differently in each class, with NNRTIs having a lower barrier to resistance than PIs. Management of treatment-experienced patients is complex and there are often limited treatment options. The choice of viable CART should be made by reviewing resistance reports, ARV history and the ability of patients 2 × NRTI*† + 1 × NNRTI OR 2 × NRTI* + 1 × boosted PI OR 1 × NNRTI + 1 × boosted PI‡ + 1–2 × NRTI* Change all medicines if possible and a resistance test is recommended * Change to new and active NRTIs guided by resistance testing † This could lead to rapid development of resistance to NNRTIs if potential exists for NRTI cross-resistance ‡ Studies with a low-dose ritonavir-boosted PI + an NNRTI have shown good results NRTI = Nucleoside/tide reverse transcriptase inhibitor NNRTI = Non-nucleoside reverse transcriptase inhibitor PI = Protease inhibitor CP, Oct, p393-99, CF2 24/9/09 11:58 Page 397 Vol 1 Box 7: Examples of interactions with ARVs CLASS DRUG NAME Boosted PIs increase rifabutin levels Reduce rifabutin dose (150mg on alternate days) NNRTIs can reduce rifabutin levels Consider increasing rifabutin dose (450mg once daily) Etravirine and rifabutin levels reduced when used together Use with caution. Therapeutic drug monitoring (TDM) advised Reduces levels of NNRTIs and all boosted PIs Consider increased dose of efavirenz and nevirapine (TDM advised). Contraindicated with PIs Reduces levels of raltegravir Increase raltegravir dose Reduces levels of maraviroc Increase maraviroc dose Ritonavir increases itraconazole exposure Avoid high doses of itraconazole Efavirenz, etravirine and nevirapine reduce itraconazole levels Consider increased dose or alternative, monitor for clinical effect Maraviroc levels increased Reduce maraviroc dose H2-receptor blocker Reduces atazanavir levels Administer 2–12 hours after atazanavir; not within 12 hours before Proton pump inhibitors Reduces atazanavir levels Avoid co-administration, use alternative Simvastatin Levels increased by PIs leading to increased toxicity Avoid co-administration, use alternative Pravastatin Levels raised when combined Use lowest dose and titrate with boosted darunavir in up minority of subjects St John’s wort Reduces concentrations of boosted PIs and NNRTIs Avoid co-administration MDMA (“ecstasy”) Ritonavir can increase concentrations of MDMA Advise to avoid Methadone Ritonavir and NNRTIs can reduce methadone levels Monitor for withdrawal symptoms, increase dose as needed over several days Sildenafil and other PDE5 inhibitors Ritonavir increases sildenafil concentrations Reduce sildenafil dose. Advise patient not to repeat dose for 72 hours Warfarin Ritonavir reduces effect of warfarin. Efavirenz and nevirapine have unpredictable effect on warfarin Frequent INR monitoring initially, titrate dose accordingly Fluticasone (inhaled or nasal) Increased systemic absorption with ritonavir Risk of steroid toxicity. Avoid, use alternative Anti-infectives Rifampicin Itraconazole Antacids Statins Illicit Herbal Others Perhaps the most effective intervention to prevent HIV transmission has been the implementation of antenatal HIV screening. HIV-infected women are identified, and receive ARV therapy and other measures to prevent mother-to-child transmission. Pregnant women already receiving CART before conception can continue on their current regimens. In some situations CART may be modified to avoid ARVs with limited evidence for use in pregnancy. For women who have not required CART for their own health, treatment is initiated after the first trimester. The newborn also receives ARVs — this can range from mono- or dual therapy to CART depending on the risk of transmission related to the maternal VL, labour and birth. With effective treatment transmissions are rare. (BHIVA pregnancy guidelines are available at www.bhiva.org.) Monitor. Consider dose reduction of clarithromycin in renal impairment. Consider alternative antibiotic Consider azithromycin following steps to ensure patients with HIV are not affected by interactions with ARVs: Pregnancy ACTION REQUIRED Reduced clarithromycin levels with NNRTIs Rifabutin Clinical practice points Pharmacists should take the ● Check medication histories — identify patients at risk of clinically significant drug interactions regardless of clinical setting ● Check for other medicines — this should include over-the-counter, herbal and recreational drugs, as well as medicines purchased through the internet ● Check for interactions — the British National Formulary provides basic information on important drug interactions; a Liverpool University website expands on this and is a useful internet reference source (Box 8, p399) ● Provide advice or refer — all clinically significant interactions identified should be acted upon by contacting the prescriber or the pharmacy at the patient’s HIV centre INTERACTION WITH ARV Clarithromycin Increased clarithromycin exposure with ritonavir. Increased clarithromycin exposure with atazanavir Drug-drug interactions Clinically significant drug interactions are highly prevalent among HIV-infected patients receiving CART.5 The HIV-positive population is ageing and developing significant comorbidities that require pharmaceutical intervention. Interactions can occur between commonly prescribed medicines and ARVs (Box 7). Patients may receive medicines from multiple prescribers and pharmacies, which increases the risk of drug interactions not being identified and dealt with.6 Many drug interactions are avoidable by selecting alternative medicines to allow continuation of CART. Some interactions require dose-adjustment of the coadministered medicine or components of CART. Therapeutic drug monitoring (TDM) can be a useful tool to ensure adequate levels of ARV. TDM is commercially available for PIs, NNRTIs and integrase inhibitors. Clinical Pharmacist 397 CLINICAL FOCUS to tolerate ARVs. Expert advice should be sought from virologists and experienced HIV pharmacists and medical staff. Some patients will have long-term toxicities and require adjunct therapies or ARV switches — and may be suitable for entry into clinical trials for new ARVs. October 2009 CP, Oct, p393-99, CF2 24/9/09 11:58 Page 399 Vol 1 October 2009 Clinical Pharmacist Eraxion | Dreamstime.com References 1 Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. New England Journal of Medicine 2009;360:1815–26. 2 When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352–63. 3 Strategic timing of antiretroviral treatment (START) trial. http://clinicaltrials. gov/ct2/show/NCT00867048 (accessed 10 September 2009) Hepatitis co-infection 4 British HIV Association. Treatment of HIV-1 infected adults with antiretroviral therapy 2008. www.bhiva.org (accessed 10 September 2009). Treating HIV-positive patients co-infected with hepatitis B or hepatitis C can be complex. Treatment of both HIV and hepatitis can be difficult because of overlapping toxicities of antiviral medicines. Tenofovir, lamivudine and entecavir are active against both HIV and hepatitis B. These medicines should not be administered to any hepatitis B-infected patient without first checking HIV status. HIV patients requiring active treatment for hepatitis B are recommended to start CART containing medicines active against both HIV and hepatitis B. When switching treatment it is important to confirm the patient’s hepatitis status, since removing antihepatitis B medicines can cause reactivation of the hepatitis infection. Historically many patients with hepatitis C have undergone hepatitis C treatment before commencing CART. This is mainly due to the overlapping toxicity of anti-hepatitis C medicines and ARVs. Many patients will also have been above the threshold for initiation of CART. In the future if HIV treatment is initiated earlier patients may undergo hepatitis C treatment also. Future studies aim to investigate the safety and efficacy of coadministration of ARVs and anti-hepatitis C medicines. The BHIVA hepatitis guidelines should be consulted when treating co-infected patients. 5 Miller CD, El-Kholi R, Faragon JJ, et al. Prevalence and risk factors for clinically significant drug interactions with antiretroviral therapy. Pharmacotherapy 2007;27:1379–86. 6 de Maat MM, Frankfort SV, Mathôt RA, et al. Discrepancies between medical and pharmacy records for patients on anti-HIV drugs. Annals of Pharmacotherapy 2002;36:410–5. 7 Babiker AG. An analysis of pooled data from the ESPRIT and SILCAAT studies: findings by latest CD4+ count. Abstract TUAB101. The 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa. 19–22 July 2009. 8 Tavel J. Immunologic and virologic effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy (ART): The INSIGHT STALWART Study. Abstract TUAB102. The 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa. 19–22 July 2009. Future strategies Earlier initiation of treatment is currently being studied and may lead to starting treatment much closer to HIV diagnosis. Studies have looked at treatment during seroconversion and this continues to be an area for future research. Treatment of HIV in the future will focus on minimising long-term toxicity to ARVs and managing patient comorbidities. Novel strategies currently being studied include protease inhibitor monotherapy and reverse transcriptase inhibitor-sparing regimens. These strategies aim to avoid long-term reverse transcriptase inhibitor toxicity. Pre-exposure prophylaxis (PrEP) has been studied (see p391 of accompanying article), with success in animal Box 8: Further reading and resources British HIV Association www.bhiva.org ● UK guidelines for the management of sexual and reproductive health of people living with HIV infection ● Immunisation ● Management of HIV infection in pregnant women ● HIV associated with malignancies ● Renal transplant ● Liver transplant ● Treatment guidelines for tuberculosis/HIV co-infection ● Guidelines for the management of co-infection of HIV-1 and chronic hepatitis B or C ● Guidelines for antiretroviral treatment of HIV-1 infected individuals Liverpool HIV Pharmacology Group (University of Liverpool) www.hiv-druginteractions.org ● An online drug-drug interaction resource Immunodeficiency clinic (Toronto) www.hivclinic.ca/main/drugs_interact.html ● An online drug-drug interaction resource Health Protection Agency www.hpa.org.uk ● Epidemiology Rosy Weston is senior lead pharmacist, HIV and sexual health, and Brett Marett is lead pharmacist, HIV and sexual health, both at Imperial College Healthcare NHS Trust. E: [email protected] CLINICAL FOCUS models. Further human studies are ongoing in populations with high HIV prevalence, with individuals at high risk of exposure to HIV taking ARVs to prevent infection. Studies involving the use of vaccines as both prophylaxis and therapeutic strategies are ongoing. Unpublished preliminary data from immunotherapy studies looking at boosting the immune system or surrogate markers such as the CD4 counts have had poor results in terms of treatment outcomes.7,8 Nonetheless, this area of research is important because it could delay the use of ARVs. 399