FOCUS ON HIV. By Christine Elliott, BScPhm, RPh

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Therapeutic Options FOCUS ON HIV By Christine Elliott, BScPhm, RPh BACKGROUND The human immunodeficiency virus type 1 (HIV-1) was first discovered in 1982.

1 Therapeutic Options FOCUS ON HIV By Christine Elliott, BScPhm, RPh BACKGROUND The human immunodeficiency virus type 1 (HIV-1) was first discovered in A global pandemic followed, with an estimated 37 million people infected today 2, the majority of whom (23.5 million) live in Sub-Saharan Africa. 3 The discovery of antiretroviral (ARV) drugs has changed the disease from a lethal one to one that is chronic in pathology. Worldwide, around 50% of those infected with HIV have access to ARV drugs. 2 It is estimated that at the end of 2014, 75,500 Canadians were living with HIV, with 16,020 remaining undiagnosed. 5 In Canada, the HIV population can be characterized as follows: 53% gay men and other men having sex with men 31% heterosexual 22% female 19% injection drug users 9% aboriginal people The estimated new cases per year (2,570) has remained stable, while the prevalence has increased, in part because people with HIV live longer. 5 ETIOLOGY & PATHOPHYSIOLOGY HIV is an enveloped retrovirus, spherical in shape with a spiked surface. 5 There are two types of HIV (HIV-1 and HIV-2) and several subtypes. HIV-1 is the most prevalent type. 3 After exposure to HIV, for an infection to be established, a series of complex steps between the virus, its regulatory genes and the host immune system needs to take place. 5 These steps in the host cell interaction include: Viral binding and entry that involve chemoreceptors CCR5 and CXCR4 that act as co-receptors for HIV anchorage to the host cell 5 HIV RNA replication that is mediated in part by reverse transcriptase and integrase enzymes 5 Viral assembly where the protease enzyme plays a role 5 Budding and release of new virions 5 Many of the steps in the HIV life cycle have been used as targets for antiretroviral drugs. 5 The virus has a high affinity for CD4, a receptor that is found on T cells, and also on the surface of monocytes, dendritic cells and brain microglia. 5 The virus, or infected cells can cross the epithelial barrier in a few hours and into local lymph nodes in 3 to 6 days. 3 It is disseminated quickly in the blood with a viral reservoir forming in CD4 T cells. 3 There is a small subset of the HIV population (about 3 to 5%) called long-term non-progressors, who maintain normal CD4 cell counts for many years, but eventually will progress to AIDS if untreated. Another subset (around 1%), called an elite controller, can maintain a suppressed viral load for years and is at low risk of developing AIDS. 5 RISK FACTORS HIV is transmitted through direct contact and exchange of bodily fluids like blood, semen, pre-seminal fluid, rectal fluids, vaginal fluids, and breast milk with an infected person. The virus is not transmitted via saliva, tears or sweat. HIV does not survive long and cannot replicate outside of the body. 6 The risk of HIV transmission via different methods is presented in Table 1. SIGNS & SYMPTOMS Stage 1: Acute Retroviral Syndrome (ARS) 7 2 to 4 weeks after infection 3,7 34 to 60% of people will feel flu-like symptoms, others are asymptomatic 3,7 Viral replication and risk of transmission are high CD4 counts can decrease dramatically because the virus uses and destroys them during replication 6 A normal CD4 count in a non-infected person is 700 to 1100 cells/mm. 8 Stage 2: Clinical Latency Starts about 100 days after initial infection, lasts on average 5 to 8 years if untreated or for decades if treated 3,7 Immune system responds, HIV replication slows 3 CD4 increases to levels below pre-infection levels 7 Transmission is possible, and the I

2 TABLE 1: Risk of HIV transmission 7 Method Risk (%) Comment Occupational injury 0.2 Post-exposure antiretroviral therapy (ART) for 28 days is standard treatment 3 Sexual IV drug use Perinatal Reduced to 1-2(%) with maternal ART prophylaxis 3 Parenteral 90 * Up to 50% of transmissions may occur from the source patient whose viral load is high during the early stages of infection. 7 individual may remain symptom free At the end of this stage, the immune system weakens, the viral level increases, the CD4 count decreases and HIV symptoms may reoccur 6 Stage 3: Acquired Immune Deficiency Syndrome (AIDS) Diagnosed by a CD4 count < 200 cells/mm 6 or the development of certain opportunistic illnesses Without treatment, the life expectancy is 3 years 6 Diagnosis of HIV infection is confirmed by blood tests, testing for the presence of anti-hiv antibodies and antigens. After initial infection, the antibodies may not be detectable in the blood stream for about 17 to 18 days. 7 Any patients who test negatively for HIV but presents with symptoms consistent with HIV, should be tested for HIV-2 or other HIV variants not well detected by standard testing. 3 CD4 count and plasma HIV RNA (viral load) are measured at baseline and periodically, to guide treatment. 1,5,7 PHARMACOTHERAPY Antiretroviral therapy (ART) refers to combination treatment with three or more antiretroviral drugs. 9 Patients who present late for treatment are at higher risk for mortality, incur higher treatment costs and are less likely to remain in care. 9 While many guidelines have previously listed CD4 count < 350 cells/mm 3 as a threshold for initiating ART, current thinking is to treat all HIV seropositive individuals, regardless of CD4 count. 9 Untreated HIV may lead to cardiovascular disease, kidney disease, liver disease, and several types of cancer and neurocognitive disorders in patients who do not have AIDS. A list of currently available ARV drugs is listed in Table 2. Some ARV drugs may elevate lipids (except triglycerides in women), exacerbating the increased risk of cardiovascular disease and diabetes mellitus from HIV. 7 Postmenopausal osteopenia and osteoporosis in women may be exacerbated by HIV and ART. 7 Renal function and liver testing should be measured at baseline, after one month on ART, then every 3 to 4 months for two years. After two years of therapy, testing can be repeated every 6 months. 7 Lipids and blood glucose should be measured at baseline, after one month of ART and then every 6 months thereafter. 7 TABLE 2: Major antiretroviral drugs 5,10,11 Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) abacavir (ABC) 300 BID or 600 daily Avoid if HLA-B*5701 positive didanosine (ddi) 400 daily Empty stomach emtricitabine (FTC) lamivudine (3TC) 200 daily (available in combination only) 150 BID or 300 daily stavudine (d4t) 40 BID 30 mg BID if weight <60kg WHO recommends 30 mg BID irrespective of body weight tenofovir DF (TDF) (NtRTI) zidovudine (AZT) 300 daily 300 BID or 200 TID NRTI combination products emtricitibine-tenofovir DF abacavir-lamivudine zidovudine-lamivudine zidovudine-lamivudine-abacavir 1 tablet daily 1 tablet daily 1 tablet BID 1 tablet BID Mechanism of Action: Competitively binds to the viral enzyme reverse transcriptase, inhibiting viral replication. 12 Forms the backbone of therapy for initial treatment. Protocols recommend two NRTIs/NtRTIs in combination plus additional antiretroviral(s) Advantages: Easy dosing schedule, long half-life, food has minimal effect, fewer drug interactions. Disadvantages: Potential for drug interactions, cross resistance and transmission of resistance. Drug Interactions: Tenofovir DF: didanosine; caution with nephrotoxic drugs Adverse Effects a : Emtricitabine and lamivudine have minimal toxicity. Emtricitabine, lamivudine, tenofovir may exacerbate hepatitis in patients with hepatitis B who discontinue the drug. Hypersensitivity reactions (increased risk in patients with the human leukocyte antigen (HLA)-B*5701 allele with abacavir). II

3 TABLE 2 - continued: Major antiretroviral drugs 5,10,11 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) delaviridine (DLV) 400 TID efavirenz (EFV) 600 daily Take at bedtime, empty stomach etravirine (ETR) 200 BID Take with food nevirapine (NVP) 200 BID or 400 daily Starting dose 200 mg daily x 14 days rilpivirine (RPV) 25 daily Take with food Mechanism of Action: Selectively binds to the viral enzyme reverse transcriptase, preventing RNA and DNA-dependent viral replication. 13 Advantages: Low toxicity, good long-term results, less lipid effects, no food effects, saves PIs for future use Disadvantages: Low genetic barrier for mutation, cross-resistance, potential for drug-drug interactions Drug Interactions: CYP450 metabolized drugs for all; proton pump inhibitors for rilpivirine Adverse Effects a : Rash, Stevens-Johnson syndrome (nevirapine, etravirine, delaviridine), hepatitis (nevirapine), potential teratogen (efavirenz) Protease Inhibitors (PIs) PIs have low bioavailability and are co-administered with a pharmacologic booster such as ritonavir or cobicistat (separate dosage forms unless otherwise indicated) atazanavir (ATV) 400 daily Take with food atazanavir/ritonavir (ATV/r) 300/100 daily Take with food darunavir/ritonavir (DRV/r) 800/100 daily Take with food darunavir-cobicistat (DRV/c) 800/150 daily (1 tablet) Take with food; avoid taking with tenofovir if egfr<70 ml/min fosamprenavir/ritonavir (FPV/r) 1400/100 daily Take with food (with ritonavir tablets) indinavir/ritonavir (IDV/r) 800/100 BID Fluid intake 1.5L/24 hours lopinavir-ritonavir (LPV/r) 800/200 daily or 400/100 BID Take with food nelfinavir (NFV) 1250 BID or 750 TID Take with food saquinavirhg/ritonavir (SQV/r) 1000/100 BID Take with food tipranavir/ritonavir (TPV/r) 500/200 BID Take with food (with ritonavir tablets) Mechanism of Action: Binds to the site of HIV-1 protease activity, preventing viral protein cleavage and reassembly, resulting in viral particles that are immature and non infectious 14 Advantages: High genetic threshold, useful for ART experienced patients with NNRTI drug resistance Disadvantages: Complex food requirements, common cross resistance, drug interactions, class side effects (e.g. cardiac conduction effects, nausea, diarrhea, insulin resistance, hyperglycemia, fat maldistribution and dyslipidemia) Drug interactions: All except nelfinavir: CYP450 metabolized drugs; atazanavir: proton pump inhibitors and tenofovir Adverse Effects a : Elevated serum transaminase, increased bleeding in hemophiliacs (saquinavir-hg/ritonavir, nelfinavir, indinavir/ritonavir, fosamprenavir/ritonavir), QTc interval prolongation (lopinavir-ritonavir) Integrase Strand Transfer Inhibitors (INSTIs) dolutegravir (DTG) 50 daily elvitegravir (EVG) 150 daily b Take with food 15 raltegravir (RAL) 400 BID Adverse Effects a : Stevens-Johnson syndrome, CPK elevation, rhabdomyolysis (all for raltegravir only) Mechanism of Action: Inhibits the enzyme integrase, preventing the integration of viral DNA into host genomic DNA and blocking the production of new virions. Advantages: Useful for treatment experienced patients with drug resistance, few food effects, fewer adverse reactions and drug interactions Disadvantages: Lower genetic barrier for mutations than PIs Drug interactions: Rifampin, metformin, iron, calcium, magnesium, aluminum Fusion Inhibitor enfuvirtide (ENF or T20) 90 SubQ BID inject into upper arm, anterior thigh or abdomen 16 Mechanism of action: Inhibits the fusion of HIV-1 cellular membrane to the host cell membrane and thus prevents the entry of HIV-1 into the host cell 16 Advantages: Useful for treatment experienced patients with drug resistance Disadvantages: Efficacy in treatment naive patients not established Drug Interactions: none known 16 Adverse Effects a : kidney dysfunction, bacterial pneumonia III

4 TABLE 2 - continued: Major antiretroviral drugs 5,10,11 Entry Inhibitor/CCR5 Antagonist maraviroc (MVC) 150, 300, 600 BID Mechanism of action: Selectively binds to human chemokine CCR5 co-receptor on the host cell and prevents entry of the CCR5-tropic HIV-1 viral strain using that co-receptor. 17 Advantages: Useful for patients infected with only CCR5-tropic HIV-1 Disadvantages: Requires viral tropism assay, not effective against infections with dual/mixed or CXCR4-tropic HIV-1 Drug Interactions: CYP450, multiple interactions with antiretrovirals Adverse Effects a : abdominal pain, cough, dizziness, rash, pyrexia, hepatotoxicity, orthostatic hypotension, upper respiratory tract infections BID: two times daily, TID: three times daily, SubQ: subcutaneous a For a complete list of side effects, consult the product monograph b Elvitegravir is indicated in combination with a ritonavir-boosted PI. If used in combination with atazanavir/ritonavir or lopinavir/ritonavir, the dose of elvitegravir is 85 mg daily COMBINATION THERAPY The impetus behind the use of combination therapy was the development of resistance to antiretroviral monotherapy. Many drugs have specifically been developed for use in combination. Some recommended combinations are listed in Table 3. NONPHARMACOLOGIC INTERVENTIONS/PREVENTION To prevent transmission from organ and blood donation, HIV screening of donors has been performed since 1985, and HIV molecular detection screening in blood donors since Clinical trials in Africa have demonstrated that male circumcision reduces the risk of female-to-male sexual transmission by about 60%. Oral pre-exposure prophylaxis (PrEP) of ARV is recommended for uninfected people who are at substantial risk of HIV infection: men who have sex with men, transgender people, and heterosexual partners of HIV positive people who may be undiagnosed or untreated. 9 WHO prevention guidelines recognizes that any individual at substantial risk, even outside of the aforementioned populations may be a candidate for PrEP. 9 PrEP regimens of tenofovir or tenofovir+emtricitabine are similarly protective with no difference in efficacy by age, gender or mode of acquiring HIV (rectal, penile or vaginal). One meta-analysis showed a 51% reduction in the rate of transmission of HIV with PrEP compared to placebo. Adherence was critical for the rate reduction. Adverse events were similar compared with placebo. Drug resistance was very TABLE 3: Preferred regimen for the initial treatment of HIV infection in adults 7,10,18 Therapeutic Guideline NRTI Backbone Third Agent British Columbia Centre for Excellence in HIV/AIDS World Health Organization (WHO) United States Department of Health and Human Services (DHHS) Panel TDF+FTC (or 3TC) ABC a +3TC Alternate first line AZT + 3TC ABC a +3TC TDF+FTC TDF+FTC a only for patients who are HLA-B*5701 negative b refers to efavirenz 400 mg dosing c only for patients with pre-treatment estimated CrCl 70 ml/min low at 0.1%. 9 There are significant issues in implementing PrEP such as cost, equal access, and acceptability. WHO will publish guidance on implementation of PrEP in A number of topical microbicides with various chemistries and mechanisms of action (including ARVs) are in various stages of clinical development. It is anticipated that a topical product will provide a feasible option, particularly for women in poor areas, to prevent HIV infection. 1,19 A mathematical model showed that a combination of HIV screening, early ART, male circumcision, the use of microbicides and PrEP can avert 62% of HIV infections. 5 A combination of preventative measures and the development of new treatments may lead to the global goal of net zero new HIV infections. References EFV or ATV/r EFV or ATV/r EFV EFV or NVP DTG EFV400 b NVP DTG DTG or EVG/c c or RAL DRV/r 1. Pirrone V, Thakkar N, Jacobson JM, Wigdahl B, Krebs FC. Combinatorial approaches to the prevention and treatment of HIV-1 infection. Antimicrob Agents Chemother May;55(5): World Health Organization. HIV/AIDS. [internet] [cited Jan 21, 2016] Available from: 3. Brun-Vézinet F, Charpentier C. Update on the human immunodeficiency virus. Med Mal Infect May;43(5): Catie Canada s Source for HIV and Hepatitis C information. The Epidemiology of HIV in Canada. [Internet] [Published 2015; cited 2015 Nov 24]. Available from: epidemiology/epidemiology-hiv-canada 5. Younai FS. Thirty years of the human immunodeficiency virus epidemic and beyond. Int J Oral Sci Dec;5(4): IV

5 6. Centers for Disease Control and Prevention. About HIV/AIDS [Internet] [Updated Jan 16, 2015; cited 2015 Nov 25]. Available from: British Columbia Centre for Excellence in HIV/AIDS. Primary Care Guidelines for the Management of HIV/AIDS in British Columbia. [Internet] [Updated August 2015; cited 2015 Nov 27]. Available from: ubc.ca/therapeutic-guidelines/primary-care 8. Catie Canada s Source for HIV and Hepatitis C information. The Epidemiology of HIV in Canada. Treatment Update 210 [Internet] [Published 2015; cited 2015 Nov 24]. Available from: treatmentupdate/treatmentupdate-210/ anti-hiv-therapy/new-ideas-about- cd4-cell-counts-and-when-start- 9. World Health Organization. Guideline on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. [Internet] [Published Sept 2015; cited 2015 Nov 26]. pub/guidelines/earlyrelease-arv/en/ 10. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of anti-retroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. [Internet] [Updated November 2015; cited 2015 Nov 27]. Available from: adult-and-adolescent-arv-guidelines/11/ what-to-start 14. Saquinavir Drug Information Lexicomp. In: UpToDate, Waltham, MA. (Accessed 2015 Nov 30) 15. Gilead Sciences Canada Inc. Vitekta (elvitegravir). Product Monograph, Mississauga, ON, Aug 23, Hoffman La-Roche Limited. Fuzeon (enfuvirtide). Product Monograph, Mississauga, ON, March 6, ViiV Healthcare ULC. Celsentri (maraviroc). Product Monograph, Montreal QC, Jan 26, World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. What s New November 2015 [Internet] [Published Nov 2015; cited 2015 Nov 26]. Available from: bitstream/10665/198064/1/ _ eng.pdf?ua=1 19. World Health Organization. HIV/AIDS. Microbicides. [Internet] [cited Dec 4, 2015] Available from: topics/microbicides/microbicides/en/ 11. British Columbia Centre for Excellence in HIV/ AIDS. Therapeutic Guidelines for Antiretroviral Therapy (ART) of Adult HIV Infection. [Internet] [Updated September 2015; cited 2015 Nov 27]. Available from: ubc.ca/therapeutic-guidelines/adult 12. Fletcher CV. Pharmacology of nucleoside reverse transcriptase inhibitors. In: UpToDate, Bartlett JG, Mitty J (Eds), UpToDate, Waltham, MA. (Accessed 2015 Nov 30) 13. ViiV Healthcare ULC. Rescriptor (delavirdine mesylate). Product Monograph, Montreal QC, Dec 15, 2009 Reviewed by: Victoria Ip, BScPhm RPh CGP and Rob Rementilla BScPhm RPh Disclaimer: The Drug Information and Resource Centre (DIRC) of the Ontario Pharmacists Association provides this material to health professionals for informational purposes only. It is provided without warranty of any kind by DIRC and DIRC assumes no responsibility for any errors, omissions or inaccuracies therein. It is the responsibility of the health professional to use professional judgment in evaluating this material in light of any relevant clinical or situational data. This information is up to date as at the date of publication. Readers are encouraged to confirm information with additional resources. V

Continuing Education for Pharmacy Technicians

Continuing Education for Pharmacy Technicians HIV/AIDS TREATMENT Michael Denaburg, Pharm.D. Birmingham, AL Objectives: 1. Identify drugs and drug classes currently used in the management of HIV infected