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RECENT RETROVIRAL DISEAAE GUIDELINES

This document provides guidelines for the management of persons living with HIV, including recommendations for antiretroviral therapy (ART). It discusses the goals of ART which are to suppress HIV viral load, improve CD4 counts, delay drug resistance, and confer clinical benefits. Initiation of ART is recommended for all individuals regardless of CD4 count to reduce morbidity and mortality and prevent transmission. First-line regimens usually consist of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or protease inhibitor (PI) with a booster. Adherence counseling and management of comorbid

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MANAGEMENT GUIDELINES FOR PERSONS LIVING WITH HIV Presenter: Dr. Ashutosh
■ Antiretroviral therapy (ART) has reduced HIV-related morbidity and mortality at all stages of HIV infection and has reduced HIV transmission. Maximal and durable suppression of plasma viremia delays or prevents the selection of drug-resistance mutations, preserves or improves CD4 T lymphocyte (CD4) cell numbers, and confers substantial clinical benefits, all of which are important treatment goals. ■ HIV suppression with ART may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in cohorts with HIV. Despite these benefits, eradication of HIV infection cannot be achieved with available antiretrovirals (ARVs). Treatment interruption has been associated with rebound viremia, worsening of immune function, and increased morbidity and mortality.
Initiation of Antiretroviral Therapy (Last updated October 17, 2017; last reviewed October 17, 2017) ■ Antiretroviral therapy (ART) is recommended for all individuals with HIV, regardless of CD4 T lymphocyte cell count, to reduce the morbidity and mortality associated with HIV infection (AI). ■ ART is also recommended for individuals with HIV to prevent HIV transmission (AI). ■ When initiating ART, it is important to educate patients regarding the benefits and considerations of ART, and to address strategies to optimize adherence. On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but therapy should be initiated as soon as possible. ■ Rating of Recommendations: A = Strong; B = Moderate; C = Optional ■ Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long- term clinical outcomes; III = Expert opinion
■ Without antiretroviral therapy (ART), most individuals with HIV will eventually develop progressive immunodeficiency marked by CD4 T lymphocyte (CD4) cell depletion and leading to AIDS-defining illnesses and premature death. ■ The primary goal of ART is to prevent HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication to sustain plasma HIV-1 RNA (viral load) below limits of quantification by commercially available assays. ■ Durable viral suppression improves immune function and overall quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. ■ Furthermore, high plasma HIV-1 RNA is a major risk factor for HIV transmission; effective ART can reduce both viremia and transmission of HIV to sexual partners Thus, a secondary goal of ART is to reduce the risk of HIV transmission.
■ Historically, individuals with HIV have had low CD4 counts at presentation to care. However, there have been concerted efforts to increase testing of at-risk individuals and to link individuals with HIV to medical care before they have advanced HIV disease. ■ Deferring ART until CD4 counts decline puts individuals with HIV at risk of both AIDS-defining and certain serious non-AIDS conditions. Furthermore, the magnitude of CD4 recovery is directly correlated with CD4 count at ART initiation. ■ Consequently, many individuals who start treatment with CD4 counts <350 cells/mm3 never achieve CD4 counts >500 cells/mm3 after up to 10 years on ART, and have a shorter life expectancy than those initiating therapy at higher CD4 count thresholds.
■ Two large, randomized controlled trials that addressed the optimal time to initiate ART—START and TEMPRANO— demonstrated approximately a 50% reduction in morbidity and mortality among individuals with HIV who had CD4 counts >500 cells/mm3 and who were randomized to receive ART immediately versus delaying initiation of ART. ■ On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors; however, therapy should be initiated as soon as possible. Patients should also understand that currently available ART does not cure HIV. To improve and maintain immunologic function and maintain viral suppression, ART should be continued indefinitely.
Factors to Consider When Selecting an Initial Regimen ■ Every patient with HIV entering into care should have a complete medical history, physical examination, and laboratory evaluation and should be counselled regarding the implications of HIV infection. The following laboratory tests performed during initial patient visits can be used to stage HIV disease and to assist in the selection of ARV drug regimens: ■ HIV antibody testing (if prior documentation is not available or if HIV RNA is below the assay’s limit of detection) (AI); ■ Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine, urinalysis. (AIII); ■ Fasting blood glucose and serum lipids (AIII);
■ Two surrogate markers are routinely used to monitor patients with HIV: CD4 T lymphocyte (CD4) cell count to assess immune function and plasma HIV RNA (viral load) to assess level of HIV viremia. ■ A viral tropism assay should be performed before initiation of a CCR5 antagonist or at the time of virologic failure that occurs while a patient is receiving a CCR5 antagonist. ■ HLA-B*5701(MHC class 1 allele) testing should be performed before initiation of abacavir. ■ Patients should be screened for hepatitis B and hepatitis C virus infection before initiating ART and, if indicated, periodically after ART initiation, as treatment of these coinfections may affect the choice of ART.
■ HIV drug-resistance testing is recommended for persons with HIV at entry into care to guide selection of the initial antiretroviral therapy (ART) regimen (AII). If therapy is deferred, repeat testing may be considered at the time of ART initiation (CIII). ■ Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the reverse transcriptase (RT) and protease (PR) genes. If transmitted integrase strand transfer inhibitor (INSTI) resistance is a concern, providers should ensure that genotypic resistance testing also includes INSTI genotype testing (BIII). ■ HIV drug-resistance testing should be performed to assist in the selection of active drugs when changing ART regimens in the following patients: – In persons with virologic failure and HIV RNA levels >1,000 copies/mL (AI). – In persons with HIV RNA levels >500 copies/mL but <1,000 copies/mL, drug-resistance testing may be unsuccessful but should still be considered (BII). – Drug-resistance testing should also be performed when managing suboptimal viral load reduction (AII).
■ Specific Comorbidities or Other Conditions: – Cardiovascular disease, hyperlipidemia, renal disease, liver disease, osteopenia/osteoporosis or conditions associated with BMD loss, psychiatric illness, neurologic disease, drug abuse or dependency requiring narcotic replacement therapy – Pregnancy or pregnancy potential. – Coinfections: HBV, hepatitis C virus (HCV), TB
■ Regimen-Specific Considerations: – Regimen’s genetic barrier to resistance – Potential adverse effects – Known or potential drug interactions with other medications – Convenience (e.g., pill burden, dosing frequency, availability of Fixed-dose combination formulations, food requirements) – Cost
What to Start: Initial Combination Regimens for the Antiretroviral- Naive Patient (Last updated March 27, 2018; last reviewed March 27, 2018)■ More than 25 antiretroviral (ARV) drugs in six mechanistic classes are Food and Drug Administration (FDA)-approved for treatment of HIV infection. These six classes include: 1. The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 2. non-nucleoside reverse transcriptase inhibitors (NNRTIs), 3. protease inhibitors (PIs), 4. a fusion inhibitor (FI), 5. a CCR5 antagonist, and 6. Integrase strand transfer inhibitors (INSTIs). ■ In addition, two drugs, ritonavir (RTV or r) and cobicistat (COBI or c) are used solely as pharmacokinetic (PK) enhancers (or boosters) to improve the PK profiles of some ARV drugs (e.g., PIs and the INSTI elvitegravir [EVG]).
The initial ARV regimen for a treatment-naive patient generally consists of two NRTIs: ■ usually abacavir/ lamivudine (ABC/3TC) or ■ either tenofovir alafenamide (TAF)/emtricitabine (FTC) or ■ tenofovir disoproxil fumarate (TDF)/FTC, plus ■ a drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic (PK) enhancer (booster) (cobicistat or ritonavir). ■ As shown in clinical trials and by retrospective evaluation of cohorts of patients in clinical care, this strategy for initial treatment has resulted in suppression of HIV replication and CD4 T lymphocyte (CD4) cell increases in most persons with HIV.
Changes Since the Last Revision of the Guidelines ■ INSTI-based regimens are recommended as initial therapy for most people with HIV. In large clinical trials and in clinical practice, INSTI-based regimens have achieved high rates of virologic suppression and often have greater tolerability than PI- or NNRTI-based regimens. ■ In certain clinical situations, a PI- or an NNRTI-based regimen may be preferred. In recognition of these situations, a new category—called Recommended Initial Regimens in Certain Clinical Situations—has been added to the Guidelines.
■ Darunavir (DRV)-based regimens have been moved to the category of Recommended Initial Regimens in Certain Clinical Situations based on trials showing improved outcomes with INSTI-based regimens when compared with ritonavir-boosted darunavir (DRV/r), in part because of greater tolerability of the former. ■ Recommended NRTI combinations continue to be ABC/3TC and one of the tenofovir products—TAF or TDF—with FTC. With additional data since the last revision, the relative advantages of the two available tenofovir formulations have become clearer. ■ TAF has less bone and kidney toxicity than TDF and is therefore particularly advantageous in people with underlying bone and kidney disease or those at high risk for these conditions. TDF is associated with lower lipid levels than TAF, perhaps because TDF results in higher plasma levels of tenofovir, which lowers lipids. Safety, cost, and access are among the factors to consider in choosing between these two formulations of tenofovir.
■ The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) classifies the following regimens as Initial Regimens for Most People with HIV:  Dolutegravir/abacavir/lamivudinea—only for patients who are HLA-B*5701-negative (AI)  Dolutegravir plus tenofovir/emtricitabine(AI)  Elvitegravir/cobicistat/tenofovir/emtricitabine(AI)  Raltegravir plus tenofovir/emtricitabine (AI for tenofovir disoproxil fumarate, AII for tenofovir alafenamide)
Conditions that increase the urgency to initiate ART ■ Pregnancy ■ AIDS-defining conditions, including HIV-associated dementia (HAD) and AIDS-associated malignancies ■ Acute opportunistic infections (OIs) ■ Lower CD4 counts (e.g., <200 cells/mm3) ■ HIV-associated nephropathy (HIVAN) ■ Acute/early infection ■ HIV/hepatitis B virus coinfection ■ HIV/hepatitis C virus coinfection
ART
Nucleoside or Nucleotide Reverse Transcriptase Inhibitors
Drug Indication Dose in Combination Toxicity Zidovudine (AZT, azidothymidine, Retrovir, 3‘azido-3‘- deoxythymidine) Treatment of HIV infection in combination with other antiretroviral agents. Prevention of maternal-fetal HIV transmission 200 mg q8h or 300 mg bid Bone marrow suppression: macrocytic anemia or neutropenia Nausea, vomiting, headache, insomnia, asthenia Nail pigmentation Lactic acidosis/severe hepatomegaly with hepatic steatosis (rare) Hyperlipidemia Insulin resistance/diabetes mellitus Lipoatrophy Myopathy Lamivudine (Epivir, 2‘3‘-dideoxy-3‘- thiacytidine, 3TC) In combination with other antiretroviral agents for the treatment of HIV infection 150 mg bid 300 mg qd Minimal toxicity Severe acute exacerbation of hepatitis may occur in patients with HBV/HIV coinfection who discontinue 3TC.
Emtricitabine (FTC, Emtriva) In combination with other antiretroviral agents for the treatment of HIV infection 200 mg qd Hepatotoxicity in HBV-co-infected patients who discontinue drug, skin discoloration Abacavir (Ziagen) For treatment of HIV infection in combination with other antiretroviral agents 300 mg bid 600mg od Hypersensitivity reaction In HLA- B5701+ individuals (can be fatal); fever, rash, nausea, vomiting, malaise or fatigue, and loss of appetite Increased risk of MI Tenofovir (Viread) For use in combination with other antiretroviral agents when treatment is indicated 300 mg qd Rena insufficiencyl, osteomalacia, flare of hepatitis in HBV- co-infected patients who discontinue drug
Didanosine (ddI) Videx Videx EC Currently not recommended Body Weight ≥60 kg: • 400 mg once daily With TDF: • 250 mg once daily Body Weight <60 kg: • 250 mg once daily With TDF: • 200 mg once daily Pancreatitis Peripheral neuropathy Retinal changes, optic neuritis Lactic acidosis with hepatic steatosis with or without pancreatitis. Nausea, vomiting Potential association with noncirrhotic portal hypertension; ,increased risk of MI, Insulin resistance. Stavudine (d4T) Zerit Currently not recommended Body Weight ≥60 kg: • 40 mg BID Body Weight <60 kg: • 30 mg BID Peripheral neuropathy Lipoatrophy Pancreatitis Lactic acidosis/severe hepatomegaly with hepatic steatosis Hyperlipidemia Insulin resistance/diabetes mellitus Rapidly progressive ascending neuromuscular weakness
Non-Nucleoside Reverse Transcriptase Inhibitors
Nevirapine (Viramune) In combination with other antiretroviral agents for treatment of progressive HIV infection 200 mg/d × 14 days then 200 mg bid or 400 mg extended release qd Skin rash including SJS, hepatotoxicity Efavirenz (Sustiva) For treatment of HIV infection in combination with other antiretroviral agents 600 mg qhs Rash, dysphoria, elevated liver function tests, drowsiness, abnormal dreams, depression, lipid abnormalities, potentially teratogenic QT interval prolongation
Etravirine (Intelence) In combination with other antiretroviral agents in treatment- experienced patients whose HIV is resistant to non- nucleoside reverse transcriptase inhibitors and other anti- retroviral medications 200 mg bid Rash, SJS, nausea, hypersensitivity reactions Rilpivirine (Edurant) In combination with other drugs in previously untreated patients when treatment is indicated. 25 mg qd Nausea, dizziness, somnolence, vertigo, less CNS toxicity and rash than Efavirenz QT interval prolongation
Protease Inhibitors
Lopinavir/ Ritonavir (LPV/r) Kaletra In combination with other antiretroviral agents for treatment of HIV infection when treatment is warranted (LPV 400 mg + RTV 100 mg) BID, or (LPV 800 mg + RTV 200 mg) once daily Nausea, abdominal pain, hyperglycemia, fat redistribution, lipid abnormalities, may alter levels of many other drugs, paresthesias, hepatitis PR interval prolongation QT interval prolongation and torsades de pointes Atazanavir (Reyataz) For treatment of HIV infection in combination with other antiretroviral agents 400 mg qd or 300 mg qd + ritonavir 100 mg qd when given with efavirenz Hyperbilirubinemia, PR prolongation, nausea, vomiting, hyperglycemia, fat maldistribution, rash transaminase eleva- tions, renal stones Darunavir (Prezista) In combination with 100 mg ritonavir for combination therapy in treatment- experienced adults 600 mg + 100 mg ritonavir twice daily with food Diarrhea, nausea, headache, skin rash, hepatotoxicity, hyperlipidemia, hyperglycemia
Fosamprenavi r (FPV) Lexiva (a prodrug of APV) In ARV-Naive Patients: FPV 1400 mg BID, or (FPV 1400 mg + RTV 100–200 mg) once daily, or (FPV 700 mg + RTV 100 mg) BID Skin rash (12% to 19%): FPV has a sulfonamide moiety. Diarrhea, nausea, vomiting Headache Hyperlipidemia Serum transaminase elevation Hyperglycemia Fat maldistribution Possible increased bleeding episodes in patients with hemophilia Nephrolithiasis Saquinavir (SQV) Invirase (SQV 1000 mg + RTV 100 mg) BID GI intolerance, nausea, and diarrhea Headache Serum transaminase elevation Hyperlipidemia Hyperglycemia Fat maldistribution Possible increased bleeding episodes in patients with hemophilia PR interval prolongation QT interval prolongation. Torsades de pointes have been reported. Tipranavir (TPV) Aptivus (TPV 500 mg + RTV 200 mg) BID Hepatotoxicity ,Skin rash Rare cases of fatal and nonfatal intracranial hemorrhages have been reported.
■ Other Protease inhibitors are: ■ Indinavir (IDV) Crixivan ■ Nelfinavir (NFV) Viracept
Entry Inhibitors
Enfuvirtide (Fuzeon) In combination with other agents in treatment- experienced patients with evidence of HIV-1 replication despite ongoing anti- retroviral therapy 90 mg SC bid Local injection reactions, hypersensitivity reactions, increased rate of bacterial pneumonia Maraviroc (Selzentry) In combination with other antiretroviral agents in adults infected with only CCR5-tropic HIV-1 150–600 mg bid depending on con- comitant medica- tions Hepatotoxicity, nasopharyngitis, fever, cough, rash, abdominal pain, dizziness, musculo- skeletal symptoms Orthostatic hypotension, especially in patients with severe renal insufficiency
Integrase Inhibitor
Raltegravir (Isentress) In combination with other antiretroviral agents 400 mg bid Nausea, headache, diarrhea, CPK elevation, muscle weakness, rhabdomyolysis depression Elvitegravir (Available only in com- bination with cobi- cistat, tenofovir, and emtricitabine [Stribild] Fixed-dose combination 1 tablet daily Diarrhea, nausea, upper respiratory infections, headache, depression. Dolutegravir (Tivicay) In combination with other antiretroviral agents 50 mg daily for treatment-naïve patients 50 mg twice daily for treatment- experienced patients or those also receiving efavirenz or rifampin Insomnia, headache, hyper- sensitivity reactions, hepato- toxicity, depression.
Pharmacokinetic Enhancers (Boosters) ■ PK enhancing is a strategy used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. ■ Currently, two agents are used as PK enhancers: ritonavir (RTV) and cobicistat (COBI). Both of these drugs are potent inhibitors of the CYP3A4 enzyme, resulting in higher systemic exposures of the co-administered ARV metabolized by this pathway. Importantly, RTV and COBI have different effects on other CYP- or UGT-metabolizing enzymes and drug transporters. ■ Complex or unknown mechanisms of PK-based interactions preclude extrapolation of RTV drug interactions to certain COBI interactions, such as interactions with warfarin, phenytoin, voriconazole, oral contraceptives, and certain HMG-CoA reductase inhibitors (or statins).
What Not to Use ■ Some antiretroviral (ARV) regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below. Antiretroviral Drugs Not Recommended: ■ The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: delavirdine (DLV), didanosine (ddI), indinavir (IDV), nelfinavir (NFV), and stavudine (d4T).
Antiretroviral Regimens Not Recommended ■ Monotherapy ■ Nucleoside reverse transcriptase inhibitor (NRTI) monotherapy is inferior to dual-NRTI therapy. ■ Dual-NRTI Regimens These regimens are inferior to triple-drug combination regimens (AI). ■ Triple-NRTI Regimens Triple-NRTI regimens have suboptimal virologic activity or a lack of data (AI).
Virologic Response Definitions ■ Virologic suppression: A confirmed HIV RNA level below the LLOD of available assays. ■ Virologic failure: The inability to achieve or maintain suppression of viral replication to an HIV RNA level <200 copies/mL. ■ Incomplete virologic response: Two consecutive plasma HIV RNA levels ≥200 copies/mL after 24 weeks on an ARV regimen in a patient who has not yet had documented virologic suppression on this regimen. ■ Virologic rebound: Confirmed HIV RNA ≥200 copies/mL after virologic suppression. ■ Virologic blip: After virologic suppression, an isolated detectable HIV RNA level that is followed by a return to virologic suppression. ■ Low-level viremia: Confirmed detectable HIV RNA <200 copies/mL.
Virologic Failure ■ Evaluation of virologic failure should include an assessment of adherence, drug-drug or drug-food interactions, drug tolerability, HIV RNA and CD4 T lymphocyte (CD4) cell count trends over time, ART history, and prior and current drug-resistance testing results. ■ Drug-resistance testing should be performed while the patient is taking the failing antiretroviral (ARV) regimen (AI) or within 4 weeks of treatment discontinuation (AII). Even if more than 4 weeks have elapsed since ARVs were discontinued, resistance testing can still provide useful information to guide therapy, although it may not detect previously selected resistance mutations (CIII). ■ The goal of treatment for ART-experienced patients with drug resistance who are experiencing virologic failure is to establish virologic suppression (i.e. HIV RNA below the lower limits of detection of currently used assays) (AI).
■ A new regimen should include at least two, and preferably three, fully active agents (AI). A fully active agent is one that is expected to have uncompromised activity on the basis of the patient’s ART history and his or her current and past drug-resistance testing results. A fully active agent may also have a novel mechanism of action. ■ In general, adding a single ARV agent to a virologically failing regimen is not recommended because this may risk the development of resistance to all drugs in the regimen (BII). ■ For some highly ART-experienced patients with extensive drug resistance, maximal virologic suppression may not be possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and delay clinical progression.
■ When it is not possible to construct a viable suppressive regimen for a patient with multidrug resistant HIV, the clinician should consider enrolling the patient in a clinical trial of investigational agents or contacting pharmaceutical companies that may have investigational agents available. ■ When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs active against HBV should be continued as part of the new regimen. Discontinuation of these drugs may cause serious hepatocellular damage resulting from reactivation of HBV. ■ Discontinuing or briefly interrupting therapy may lead to a rapid increase in HIV RNA, a decrease in CD4 cell count, and an increase in the risk of clinical progression. Therefore, this strategy is not recommended in the setting of virologic failure (AI).
Regimen Switching in the Setting of Virologic Suppression ■ As with ART-naive patients, the use of a three-drug combination regimen is generally recommended when switching patients with suppressed viral loads to a new regimen. However, there is growing evidence that certain two-drug regimens can maintain virologic suppression. ■ Monotherapy with either a boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI) has been explored in several trials or cohort studies, and has been associated with an unacceptable rate of virologic failure and the development of resistance; therefore, monotherapy as a switching strategy is not recommended (AII). ■ More intensive monitoring to assess tolerability, viral suppression, adherence, and laboratory changes is recommended during the rst 3 months after a regimen switch (AIII).
■ Within-class switches prompted by adverse events or the availability of ARVs within the same class that offer a better safety profile, reduced dosing frequency, or lower pill burden usually maintain viral suppression, provided there is no drug resistance to the new ARV. Some examples of within-class switch strategies are switching from efavirenz (EFV) to rilpivirine (RPV), from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) etc ■ Between-class switches generally maintain viral suppression, provided there is no resistance to the other components of the regimen. Some examples of between- class switch strategies are replacing a boosted PI with RPV, or replacing an NNRTI or a boosted PI with an INSTI or maraviroc (MVC). ■ When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs active against HBV infection should be continued as part of the new regimen. Discontinuation of these drugs may cause serious hepatocellular damage resulting from reactivation
Considerations for Antiretroviral Use in Special Patient Populations
Acute and Recent (Early) HIV Infection ■ Acute HIV-1 infection, the phase of HIV-1 disease immediately after infection, is typically characterized by an initial burst of viremia; although anti-HIV-1 antibodies are undetectable, HIV-1 RNA or p24 antigen is present. Recent infection is generally considered the phase up to 6 months after infection during which detectable anti-HIV-1 antibodies develop. ■ Although some patients with acute HIV-1 infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, and other symptoms, Primary care clinicians may fail to recognize acute HIV-1 infection because its manifestations are often similar to those of many other viral infections, such as influenza and infectious mononucleosis. Acute infection can also be asymptomatic.
■ Antiretroviral therapy (ART) is recommended for all individuals with HIV-1 infection (AI) including those with early HIV-1 infection. ■ Once initiated, the goal of ART is to suppress plasma HIV- 1 RNA to undetectable levels (AIII). Testing for plasma HIV-1 RNA levels, CD4 T lymphocyte counts, and toxicity monitoring should be performed as recommended for patients with chronic HIV-1 infection (AII). ■ Genotypic drug resistance testing should be performed before initiation of ART to guide the selection of the regimen (AII). ■ ART can be initiated before drug resistance test results are available. Because resistance to pharmacokinetically enhanced protease inhibitors (PIs) emerges slowly and clinically significant transmitted resistance to PIs is uncommon, a boosted darunavir (DRV) and emtricitabine (FTC) plus either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) are recommended regimens in this setting (AIII).
■ When results of drug resistance testing are available, the treatment regimen can be modified if warranted (AII). In patients without transmitted drug resistant virus, therapy should be initiated with one of the combination regimens that is recommended for patients with chronic HIV-1 infection (AIII). ■ Patients starting ART should be willing and able to commit to treatment and should understand the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may recommend that patients defer therapy because of clinical or psychosocial factors.
Adolescents and Young Adults with HIV ■ Adolescents living with HIV largely belong to two distinct groups—those who acquired HIV in infancy, and are heavily antiretroviral therapy (ART)-experienced, and those who acquired HIV more recently during their teens. ■ ART is recommended for all individuals with HIV (AI) to reduce morbidity and mortality. Thus, ART is also recommended for ART-naive adolescents. However, before initiation of therapy, adolescents’ readiness and ability to adhere to therapy within their psychosocial context need to be carefully considered as part of therapeutic decision making (AIII). ■ Once ART is initiated, appropriate support is essential to reduce potential barriers to adherence and maximize the success in achieving sustained viral suppression (AII).
■ The adolescent sexual maturity rating can be helpful to guide regimen selection for initiation of or changes in ART as recommended by either these Adult and Adolescent ARV Guidelines or the Pediatric ARV Guidelines. ■ Pediatric and adolescent care providers should prepare adolescents for the transition into adult care settings. Adult providers should be sensitive to the challenges associated with such transitions, consulting and collaborating with adolescent HIV care providers to insure adolescents’ successful transition and continued engagement in care (AIII).
Women with HIV ■ Antiretroviral therapy (ART) is recommended for all women living with HIV to improve their health and to reduce the risk of HIV transmission to HIV-uninfected sex partners (AI). ■ In pregnant women, an additional goal of therapy is to maintain a viral load below the limit of detection throughout pregnancy to reduce the risk of transmission to the fetus and newborn (AI). ■ When selecting an antiretroviral (ARV) combination regimen for a pregnant woman, clinicians should consider the available safety, efficacy, and pharmacokinetic (PK) data on use during pregnancy for each agent. The risks and benefits of ARV use during pregnancy should be discussed with all women (AIII). ■ For women taking ARV drugs that have significant PK interactions with hormonal contraceptives, an alternative or additional effective contraceptive method to prevent unintended pregnancy is recommended (AIII). Switching to an ARV drug without interactions with hormonal contraceptives may also be considered (BIII).
■ Non-pregnant women of childbearing potential should undergo pregnancy testing before initiation of efavirenz (EFV) and receive counselling about the potential risk to the fetus and desirability of avoiding conception while on EFV-based regimens (AIII). ■ Regimens that do not include EFV should be considered in women who are planning to become pregnant or are sexually active and not using effective contraception (BIII). ■ Women on a suppressive regimen containing EFV who become pregnant and present to antenatal care during the first trimester can continue EFV throughout pregnancy (CIII).
Preferred Two-NRTI Backbones ABC/3TC Available as FDC. Can be administered once daily. ABC should not be used in patients who test positive for HLA-B*5701 because of risk of hypersensitivity reaction. ABC/3TC with ATV/r or with EFV is not recommended if pretreatment HIV RNA is >100,000 copies/mL. TDF/FTC or TDF/3TC TDF/FTC available as FDC. Either TDF/FTC (coformulated) or TDF with separate 3TC can be administered once daily. Preferred PI Regimens ATV/r plus a Preferred Two-NRTI Backbone Once-daily administration. Extensive experience in pregnancy. Maternal hyperbilirubinemia; no clinically significant neonatal hyperbilirubinemia or kernicterus reported, but neonatal bilirubin monitoring recommended. DRV/r plus a Preferred Two-NRTI Backbone Better tolerated than LPV/r. PK data available. Increasing experience with use in pregnancy. Must be used twice daily in pregnancy. Preferred Integrase Inhibitor Regimen(s) RAL plus a Preferred Two-NRTI Backbone PK data available and increasing experience in pregnancy. Rapid viral load reduction (potential role for women who present for initial therapy late in pregnancy). Twice-daily dosing required.
Stopping Antiretroviral Drugs During Pregnancy ■ Discontinuation of antiretroviral (ARV) drug regimens during pregnancy may be indicated in some situations, including serious drug-related toxicity, pregnancy-induced hyperemesis unresponsive to anti-emetics, or acute illnesses or planned surgeries that preclude oral intake ■ If an ARV drug regimen must be stopped for any reason, all ARV drugs should be stopped simultaneously and ARV therapy should then be reinitiated simultaneously as soon as possible, whether restarting the same regimen or a new regimen. ■ Continuation of all drugs during the intrapartum period generally is recommended. Women who are having elective cesarean delivery can take oral medications before the procedure and restart drugs following surgery. Because most drugs are given once or twice daily, it is likely that no doses would be missed or that at most, the postpartum dose would be given a few hours late.
HIV-2 Infection ■ Compared to HIV-1 infection, the clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma HIV-2 RNA levels, and lower mortality; however, progression to AIDS does occur. ■ There have been no randomized trials addressing the question of when to start antiretroviral therapy (ART) or the choice of initial or second-line therapy for HIV-2 infection; thus, the optimal treatment strategy has not been de ned. ■ Although the optimal CD4 T lymphocyte (CD4) cell count threshold for initiating ART in HIV-2 infection is unknown, therapy should be started before there is clinical progression. ■ HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and to enfuvirtide; thus, these drugs should not be included in an antiretroviral regimen for a patient living with HIV-2 infection.
■ Pending more definitive data on outcomes in an ART-naive patient who has HIV-2 mono-infection or HIV-1/HIV-2 dual infection and requires treatment, an initial antiretroviral therapy regimen for these patients should include two nucleoside reverse transcriptase inhibitors plus an HIV-2 active boosted protease inhibitor or integrase strand transfer inhibitors. ■ Monitoring of HIV-2 RNA levels, CD4 cell counts, and clinical improvements can be used to assess treatment response, as is recommended for HIV-1 infection. ■ Resistance-associated viral mutations to nucleoside reverse transcriptase inhibitors, protease inhibitors, and/or integrase strand transfer inhibitors may develop in patients with HIV-2 while on therapy. However, no validated HIV-2 genotypic or phenotypic antiretroviral resistance assays are available for clinical use. ■ In the event of virologic, immunologic, or clinical failure, second-line treatment should be instituted in consultation with an expert in HIV-2 management.
HIV and the Older Patient ■ Antiretroviral therapy (ART) is recommended for all patients regardless of CD4 T lymphocyte cell count (AI). ART is especially important for older patients because they have a greater risk of serious non-AIDS complications and potentially a blunted immunologic response to ART. ■ Adverse drug events from ART and concomitant drugs may occur more frequently in older patients living with HIV than in younger patients with HIV. Therefore, the bone, kidney, metabolic, cardiovascular, and liver health of older patients should be monitored closely.
■ Polypharmacy is common in older patients with HIV; therefore, there is a greater risk of drug-drug interactions between antiretroviral drugs and concomitant medications. Potential for drug-drug interactions should be assessed regularly, especially when starting or switching ART and concomitant medications. ■ HIV experts, primary care providers, and other specialists should work together to optimize the medical care of older patients with HIV with complex comorbidities. ■ Early diagnosis of HIV and counselling to prevent secondary transmission of HIV remains an important aspect of the care of the older patient with HIV.
Hepatitis B/HIV Virus Coinfection ■ Before initiation of antiretroviral therapy (ART), all patients who test positive for hepatitis B surface antigen (HBsAg) should be tested for hepatitis B virus (HBV) DNA using a quantitative assay to determine the level of HBV replication (AIII). ■ Because emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) have activity against both HIV and HBV, an ART regimen for patients with both HIV and HBV should be include (TAF or TDF) plus (3TC or FTC) as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral (ARV) regimen (AI).
■ If TDF or TAF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive ARV regimen (BI). Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. ■ Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when given to patients with HBV/HIV-coinfection (AII). Peg-interferon alfa monotherapy may also be considered in certain patients (CII). ■ Other HBV treatment regimens, including adefovir alone or in combination with 3TC or FTC and telbivudine, are not recommended for patients with HBV/HIV coinfection (CII).
■ Discontinuation of agents with anti-HBV activity may cause serious hepatocellular damage resulting from reactivation of HBV; patients should be advised against stopping these medications and be carefully monitored during interruptions in HBV treatment (AII). ■ If ART needs to be modified due to HIV virologic failure and the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII). ■ • HBV reactivation has been observed in persons with HBV infection during interferon-free HCV treatment. For that reason, all patients initiating HCV therapy should be tested for HBV. Persons with HCV/HIV coinfection and active HBV infection (determined by a positive HBsAg test) should receive ART that includes two agents with anti-HBV activity prior to initiating HCV therapy (AIII).
Hepatitis C Virus/HIV Coinfection ■ All people with HIV should be screened for hepatitis C virus (HCV) infection (AIII). Patients at high risk of HCV infection should be screened annually and whenever incident HCV infection is suspected (AIII). ■ Antiretroviral therapy (ART) may slow the progression of liver disease by preserving or restoring immune function and reducing HIV- related immune activation and inflammation. For most persons with HCV/HIV coinfection, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be initiated in all patients with HCV/HIV coinfection, regardless of CD4 T lymphocyte (CD4) cell count (AI). ■ Initial ART regimens recommended for most patients with HCV/HIV coinfection are the same as those recommended for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, the ART and HCV treatment regimen should be selected with special consideration for potential drug-drug interactions and overlapping toxicities.
■ In patients with lower CD4 counts (e.g., <200 cells/mm3), ART should be initiated promptly (AI) and HCV therapy may be delayed until the patient is stable on HIV treatment (CIII). ■ All patients with HCV/HIV coinfection should be evaluated for HCV therapy and have their liver fibrosis stage assessed to inform the length of their therapy, ribavirin need (a concern with some regimens), and subsequent risk of hepatocellular carcinoma and liver disease complications. ■ Persons with chronic HCV/HIV coinfection should be screened for active and prior hepatitis B virus (HBV) infection by testing for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B surface (HBsAb) and core (HBcAb total or IgG). Persons who are not immune to HBV infection (HBsAb-negative) should receive anti-HBV vaccination (AIII). ■ HBV reactivation has been observed in persons with HBV infection during interferon-free HCV treatment. Accordingly, persons with HCV/HIV coinfection and active HBV infection (HBsAg-positive) should receive ART that includes two agents with anti-HBV activity prior to initiating
Tuberculosis/HIV Coinfection ■ Selection of a tuberculosis (TB)-preventive treatment for individuals living with HIV and coinfected with latent tuberculosis infection (LTBI) should be based on the individual’s antiretroviral therapy (ART) regimen as noted below: – Any ART regimen can be used when isoniazid alone is used for LTBI treatment (AII). – Only efavirenz (EFV)- or raltegravir (RAL)-based regimens (in combination with either abacavir/lamivudine [ABC/3TC] or tenofovir – disoproxil fumarate/emtricitabine [TDF/FTC]) can be used with once-weekly isoniazid plus rifapentine (AIII). – If rifampin or rifabutin is used to treat LTBI, clinicians should review Tables 18a through 18e to assess the potential for interactions – among different antiretroviral (ARV) drugs and the rifamycins (BIII).
■ All patients with both HIV and active TB who are not on ART should be started on ART as described below: • In patients with CD4 counts <50 cells/mm3: Initiate ART as soon as possible, but within 2 weeks of starting TB treatment (AI). • In patients with CD4 counts ≥50 cells/mm3: Initiate ART within 8 weeks of starting TB treatment (AIII). • In all pregnant women with HIV: Initiate ART as early as feasible, for treatment of maternal HIV infection and to prevent mother- to-child transmission (MTCT) of HIV (AIII). • In patients with tuberculous meningitis: Caution should be exercised when initiating ART early, as high rates of adverse events and deaths have been reported in a randomized trial (AI). ■ Rifamycins are critical components of TB treatment regimens and should be included for patients with both HIV and active TB, unless precluded because of TB resistance or toxicity. However, rifamycins have a considerable potential for drug- drug interactions.
Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome ■ IRIS is a clinical condition caused by ART-induced restoration of pathogen-specific immune responses to opportunistic infections such as TB, resulting in either the deterioration of a treated infection (paradoxical IRIS) or a new presentation of a previously subclinical infection (unmasking IRIS). ■ TB-associated IRIS (TB- IRIS) has been reported in 8% to more than 40% of patients starting ART after TB is diagnosed, although the incidence depends on the definition of IRIS and the intensity of monitoring. ■ Predictors of IRIS include a baseline CD4 count <50 cells/mm3; higher on-ART CD4 counts; high pre-ART and lower on-ART HIV viral loads; severity of TB disease, especially high pathogen burden; and a less than 30-day interval between initiation of TB and HIV treatments. Most IRIS in HIV/TB disease occurs within 3 months of the start of ART.
■ Manifestations of unmasking TB-IRIS are characterized by their marked inflammatory nature, such as high fever, respiratory distress, lymphadenitis, abscesses, and sepsis syndrome. Manifestations of paradoxical TB-IRIS include fevers, new or worsening lymphadenopathy, new or worsening pulmonary infiltrates, enlarging pleural effusions, and new or enlarging tuberculomas. ■ IRIS ranges from mild to severe to life-threatening. Patients with mild or moderately severe IRIS can be managed symptomatically or treated with nonsteroidal inflammatory agents. ■ Patients with more severe IRIS can be treated successfully with corticosteroids, although data on the optimal dose, duration of therapy, and overall safety and efficacy are limited. In the presence of IRIS, neither TB therapy nor ART should be stopped because both therapies are necessary for the long-term health of the patient (AIII).
Acute Opportunistic Infections and Malignancies ■ In patients who have AIDS-associated opportunistic diseases for which there is no effective therapy (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy), improvement of immune function with ART may improve disease outcomes, thus ART should be started as soon as possible. ■ For patients with mild to moderate cutaneous Kaposi’s sarcoma (KS), prompt initiation of ART alone without chemotherapy has been associated with improvement of the KS lesions, even though initial transient progression of KS lesions as a manifestation of immune reconstitution inflammatory syndrome (IRIS) can also occur. ■ Similarly, although an IRIS-like presentation of non-Hodgkin’s lymphoma after initiation of ART has been described, greater ART-mediated viral suppression is also associated with longer survival among individuals undergoing treatment for AIDS lymphoma.
■ In the setting of some OIs, such as cryptococcal and tuberculous meningitis, for which immediate ART may increase the risk of serious IRIS, a short delay before initiating ART may be warranted. ■ When ART is initiated in a patient with an intracranial infection, the patient should be closely monitored for signs and symptoms associated with IRIS. In the setting of other OIs, such as Pneumocystis jirovecii pneumonia, early initiation of ART is associated with increased survival; therefore, ART should not be delayed. ■ In patients who have active non-meningeal tuberculosis, initiating ART during treatment for tuberculosis confers a significant survival advantage; therefore, ART should be initiated
Plasma HIV-1 RNA (Viral Load) and CD4 Count Monitoring ■ Viral load is the most important indicator of initial and sustained response to ART (AI) and should be measured in all patients with HIV at entry into care (AIII), at initiation of therapy (AIII), and on a regular basis thereafter. For those patients who choose to delay therapy, repeat viral load testing while not on ART is optional (CIII). ■ The minimal change in viral load considered to be statistically significant (2 standard deviations) is a three- fold change (equivalent to a 0.5 log10 copies/mL change). ■ Optimal viral suppression is defined generally as a viral load persistently below the level of detection (HIV RNA <20 to 75 copies/mL, depending on the assay used). However, isolated blips (viral loads transiently detectable at low levels, typically HIV RNA <400 copies/mL) are not uncommon in successfully treated patients and are not predictive of virologic failure.
■ The CD4 count is used to assess a patient’s immunologic response to ART. It is also used to determine whether prophylaxis for OIs can be discontinued. ■ For most patients on therapy, an adequate response is defined as an increase in CD4 count in the range of 50 to 150 cells/mm3 during the first year of ART, generally with an accelerated response in the first 3 months of treatment. ■ Subsequent increases average approximately 50 to 100 cells/mm3 per year until a steady state level is reached. ■ Patients who initiate therapy with a low CD4 countor at an older age may have a blunted increase in their counts despite virologic suppression.
Recommendations on the Indications and Frequency of Viral Load and CD4 Count Monitoring
Poor CD4 Cell Recovery and Persistent Inflammation Despite Viral Suppression ■ Morbidity and mortality from several AIDS and non-AIDS conditions are increased in individuals with HIV despite antiretroviral therapy (ART)-mediated viral suppression, and are predicted by persistently low CD4 T lymphocyte (CD4) cell counts and/or persistent immune activation. ■ ART intensification by adding antiretroviral (ARV) drugs to a suppressive ART regimen does not consistently improve CD4 cell recovery or reduce immune activation and is not recommended (AI). ■ Monitoring markers of immune activation and inflammation is not recommended because no immunologically targeted intervention has proven to improve the health of individuals with abnormally high biomarker levels, and many markers that predict morbidity and mortality fluctuate widely in individuals (AII). ■ Because there are no proven interventions to improve CD4 cell recovery and/or inflammation, efforts should focus on addressing modifiable risk factors for chronic disease (e.g., encouraging smoking cessation, a healthy diet, and exercise; treating hypertension and hyperlipidemia) (AII).
Treatment Goals ■ After initiation of effective ART, viral load reduction to below limits of assay detection usually occurs within the first 12 to 24 weeks of therapy. Predictors of virologic success include the following: – Low baseline viremia; – High potency of the ARV regimen; – Tolerability of the regimen; – Convenience of the regimen; and – Excellent adherence to the regimen.
Post -Exposure prophylaxis ■ A 28-day course of nPEP is recommended for HIV- uninfected persons who seek care ≤ 72 hours after a non- occupational exposure to blood, genital secretions, or other potentially infected body fluids of persons known to be HIV infected or of unknown HIV status when that exposure represents a substantial risk for HIV acquisition. ■ Adults and adolescents aged ≥ 13 years, including pregnant women, with normal renal function (creat CL ≥ 60 mL/min) ■ A 3-drug regimen consisting of tenofovir DF 300 mg and fixed dose combination emtricitabine 200 mg (Truvadac) once daily with raltegravir 400 mg twice daily or dolutegravir 50 mg once daily ■ If CrCL ≤59 mL/min, A 3-drug regimen consisting of zidovudine and lamivudine, with both doses adjusted to degree of renal function with raltegravir 400 mg twice daily or dolutegravir 50 mg once daily.
References ■ Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. (March 2018) [Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) ] ■ 19th edition of Harrison’s Principles of Internal Medicine.

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RECENT RETROVIRAL DISEAAE GUIDELINES

  • 1.
    MANAGEMENT GUIDELINES FOR PERSONSLIVING WITH HIV Presenter: Dr. Ashutosh
  • 2.
    ■ Antiretroviral therapy(ART) has reduced HIV-related morbidity and mortality at all stages of HIV infection and has reduced HIV transmission. Maximal and durable suppression of plasma viremia delays or prevents the selection of drug-resistance mutations, preserves or improves CD4 T lymphocyte (CD4) cell numbers, and confers substantial clinical benefits, all of which are important treatment goals. ■ HIV suppression with ART may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in cohorts with HIV. Despite these benefits, eradication of HIV infection cannot be achieved with available antiretrovirals (ARVs). Treatment interruption has been associated with rebound viremia, worsening of immune function, and increased morbidity and mortality.
  • 3.
    Initiation of AntiretroviralTherapy (Last updated October 17, 2017; last reviewed October 17, 2017) ■ Antiretroviral therapy (ART) is recommended for all individuals with HIV, regardless of CD4 T lymphocyte cell count, to reduce the morbidity and mortality associated with HIV infection (AI). ■ ART is also recommended for individuals with HIV to prevent HIV transmission (AI). ■ When initiating ART, it is important to educate patients regarding the benefits and considerations of ART, and to address strategies to optimize adherence. On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but therapy should be initiated as soon as possible. ■ Rating of Recommendations: A = Strong; B = Moderate; C = Optional ■ Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long- term clinical outcomes; III = Expert opinion
  • 4.
    ■ Without antiretroviraltherapy (ART), most individuals with HIV will eventually develop progressive immunodeficiency marked by CD4 T lymphocyte (CD4) cell depletion and leading to AIDS-defining illnesses and premature death. ■ The primary goal of ART is to prevent HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication to sustain plasma HIV-1 RNA (viral load) below limits of quantification by commercially available assays. ■ Durable viral suppression improves immune function and overall quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. ■ Furthermore, high plasma HIV-1 RNA is a major risk factor for HIV transmission; effective ART can reduce both viremia and transmission of HIV to sexual partners Thus, a secondary goal of ART is to reduce the risk of HIV transmission.
  • 5.
    ■ Historically, individualswith HIV have had low CD4 counts at presentation to care. However, there have been concerted efforts to increase testing of at-risk individuals and to link individuals with HIV to medical care before they have advanced HIV disease. ■ Deferring ART until CD4 counts decline puts individuals with HIV at risk of both AIDS-defining and certain serious non-AIDS conditions. Furthermore, the magnitude of CD4 recovery is directly correlated with CD4 count at ART initiation. ■ Consequently, many individuals who start treatment with CD4 counts <350 cells/mm3 never achieve CD4 counts >500 cells/mm3 after up to 10 years on ART, and have a shorter life expectancy than those initiating therapy at higher CD4 count thresholds.
  • 6.
    ■ Two large,randomized controlled trials that addressed the optimal time to initiate ART—START and TEMPRANO— demonstrated approximately a 50% reduction in morbidity and mortality among individuals with HIV who had CD4 counts >500 cells/mm3 and who were randomized to receive ART immediately versus delaying initiation of ART. ■ On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors; however, therapy should be initiated as soon as possible. Patients should also understand that currently available ART does not cure HIV. To improve and maintain immunologic function and maintain viral suppression, ART should be continued indefinitely.
  • 7.
    Factors to ConsiderWhen Selecting an Initial Regimen ■ Every patient with HIV entering into care should have a complete medical history, physical examination, and laboratory evaluation and should be counselled regarding the implications of HIV infection. The following laboratory tests performed during initial patient visits can be used to stage HIV disease and to assist in the selection of ARV drug regimens: ■ HIV antibody testing (if prior documentation is not available or if HIV RNA is below the assay’s limit of detection) (AI); ■ Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine, urinalysis. (AIII); ■ Fasting blood glucose and serum lipids (AIII);
  • 8.
    ■ Two surrogatemarkers are routinely used to monitor patients with HIV: CD4 T lymphocyte (CD4) cell count to assess immune function and plasma HIV RNA (viral load) to assess level of HIV viremia. ■ A viral tropism assay should be performed before initiation of a CCR5 antagonist or at the time of virologic failure that occurs while a patient is receiving a CCR5 antagonist. ■ HLA-B*5701(MHC class 1 allele) testing should be performed before initiation of abacavir. ■ Patients should be screened for hepatitis B and hepatitis C virus infection before initiating ART and, if indicated, periodically after ART initiation, as treatment of these coinfections may affect the choice of ART.
  • 9.
    ■ HIV drug-resistancetesting is recommended for persons with HIV at entry into care to guide selection of the initial antiretroviral therapy (ART) regimen (AII). If therapy is deferred, repeat testing may be considered at the time of ART initiation (CIII). ■ Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the reverse transcriptase (RT) and protease (PR) genes. If transmitted integrase strand transfer inhibitor (INSTI) resistance is a concern, providers should ensure that genotypic resistance testing also includes INSTI genotype testing (BIII). ■ HIV drug-resistance testing should be performed to assist in the selection of active drugs when changing ART regimens in the following patients: – In persons with virologic failure and HIV RNA levels >1,000 copies/mL (AI). – In persons with HIV RNA levels >500 copies/mL but <1,000 copies/mL, drug-resistance testing may be unsuccessful but should still be considered (BII). – Drug-resistance testing should also be performed when managing suboptimal viral load reduction (AII).
  • 10.
    ■ Specific Comorbiditiesor Other Conditions: – Cardiovascular disease, hyperlipidemia, renal disease, liver disease, osteopenia/osteoporosis or conditions associated with BMD loss, psychiatric illness, neurologic disease, drug abuse or dependency requiring narcotic replacement therapy – Pregnancy or pregnancy potential. – Coinfections: HBV, hepatitis C virus (HCV), TB
  • 11.
    ■ Regimen-Specific Considerations: –Regimen’s genetic barrier to resistance – Potential adverse effects – Known or potential drug interactions with other medications – Convenience (e.g., pill burden, dosing frequency, availability of Fixed-dose combination formulations, food requirements) – Cost
  • 12.
    What to Start:Initial Combination Regimens for the Antiretroviral- Naive Patient (Last updated March 27, 2018; last reviewed March 27, 2018)■ More than 25 antiretroviral (ARV) drugs in six mechanistic classes are Food and Drug Administration (FDA)-approved for treatment of HIV infection. These six classes include: 1. The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 2. non-nucleoside reverse transcriptase inhibitors (NNRTIs), 3. protease inhibitors (PIs), 4. a fusion inhibitor (FI), 5. a CCR5 antagonist, and 6. Integrase strand transfer inhibitors (INSTIs). ■ In addition, two drugs, ritonavir (RTV or r) and cobicistat (COBI or c) are used solely as pharmacokinetic (PK) enhancers (or boosters) to improve the PK profiles of some ARV drugs (e.g., PIs and the INSTI elvitegravir [EVG]).
  • 13.
    The initial ARVregimen for a treatment-naive patient generally consists of two NRTIs: ■ usually abacavir/ lamivudine (ABC/3TC) or ■ either tenofovir alafenamide (TAF)/emtricitabine (FTC) or ■ tenofovir disoproxil fumarate (TDF)/FTC, plus ■ a drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic (PK) enhancer (booster) (cobicistat or ritonavir). ■ As shown in clinical trials and by retrospective evaluation of cohorts of patients in clinical care, this strategy for initial treatment has resulted in suppression of HIV replication and CD4 T lymphocyte (CD4) cell increases in most persons with HIV.
  • 14.
    Changes Since theLast Revision of the Guidelines ■ INSTI-based regimens are recommended as initial therapy for most people with HIV. In large clinical trials and in clinical practice, INSTI-based regimens have achieved high rates of virologic suppression and often have greater tolerability than PI- or NNRTI-based regimens. ■ In certain clinical situations, a PI- or an NNRTI-based regimen may be preferred. In recognition of these situations, a new category—called Recommended Initial Regimens in Certain Clinical Situations—has been added to the Guidelines.
  • 15.
    ■ Darunavir (DRV)-basedregimens have been moved to the category of Recommended Initial Regimens in Certain Clinical Situations based on trials showing improved outcomes with INSTI-based regimens when compared with ritonavir-boosted darunavir (DRV/r), in part because of greater tolerability of the former. ■ Recommended NRTI combinations continue to be ABC/3TC and one of the tenofovir products—TAF or TDF—with FTC. With additional data since the last revision, the relative advantages of the two available tenofovir formulations have become clearer. ■ TAF has less bone and kidney toxicity than TDF and is therefore particularly advantageous in people with underlying bone and kidney disease or those at high risk for these conditions. TDF is associated with lower lipid levels than TAF, perhaps because TDF results in higher plasma levels of tenofovir, which lowers lipids. Safety, cost, and access are among the factors to consider in choosing between these two formulations of tenofovir.
  • 16.
    ■ The Panelon Antiretroviral Guidelines for Adults and Adolescents (the Panel) classifies the following regimens as Initial Regimens for Most People with HIV:  Dolutegravir/abacavir/lamivudinea—only for patients who are HLA-B*5701-negative (AI)  Dolutegravir plus tenofovir/emtricitabine(AI)  Elvitegravir/cobicistat/tenofovir/emtricitabine(AI)  Raltegravir plus tenofovir/emtricitabine (AI for tenofovir disoproxil fumarate, AII for tenofovir alafenamide)
  • 17.
    Conditions that increasethe urgency to initiate ART ■ Pregnancy ■ AIDS-defining conditions, including HIV-associated dementia (HAD) and AIDS-associated malignancies ■ Acute opportunistic infections (OIs) ■ Lower CD4 counts (e.g., <200 cells/mm3) ■ HIV-associated nephropathy (HIVAN) ■ Acute/early infection ■ HIV/hepatitis B virus coinfection ■ HIV/hepatitis C virus coinfection
  • 18.
  • 19.
    Nucleoside or NucleotideReverse Transcriptase Inhibitors
  • 20.
    Drug Indication Dosein Combination Toxicity Zidovudine (AZT, azidothymidine, Retrovir, 3‘azido-3‘- deoxythymidine) Treatment of HIV infection in combination with other antiretroviral agents. Prevention of maternal-fetal HIV transmission 200 mg q8h or 300 mg bid Bone marrow suppression: macrocytic anemia or neutropenia Nausea, vomiting, headache, insomnia, asthenia Nail pigmentation Lactic acidosis/severe hepatomegaly with hepatic steatosis (rare) Hyperlipidemia Insulin resistance/diabetes mellitus Lipoatrophy Myopathy Lamivudine (Epivir, 2‘3‘-dideoxy-3‘- thiacytidine, 3TC) In combination with other antiretroviral agents for the treatment of HIV infection 150 mg bid 300 mg qd Minimal toxicity Severe acute exacerbation of hepatitis may occur in patients with HBV/HIV coinfection who discontinue 3TC.
  • 21.
    Emtricitabine (FTC, Emtriva) In combinationwith other antiretroviral agents for the treatment of HIV infection 200 mg qd Hepatotoxicity in HBV-co-infected patients who discontinue drug, skin discoloration Abacavir (Ziagen) For treatment of HIV infection in combination with other antiretroviral agents 300 mg bid 600mg od Hypersensitivity reaction In HLA- B5701+ individuals (can be fatal); fever, rash, nausea, vomiting, malaise or fatigue, and loss of appetite Increased risk of MI Tenofovir (Viread) For use in combination with other antiretroviral agents when treatment is indicated 300 mg qd Rena insufficiencyl, osteomalacia, flare of hepatitis in HBV- co-infected patients who discontinue drug
  • 22.
    Didanosine (ddI) Videx Videx EC Currentlynot recommended Body Weight ≥60 kg: • 400 mg once daily With TDF: • 250 mg once daily Body Weight <60 kg: • 250 mg once daily With TDF: • 200 mg once daily Pancreatitis Peripheral neuropathy Retinal changes, optic neuritis Lactic acidosis with hepatic steatosis with or without pancreatitis. Nausea, vomiting Potential association with noncirrhotic portal hypertension; ,increased risk of MI, Insulin resistance. Stavudine (d4T) Zerit Currently not recommended Body Weight ≥60 kg: • 40 mg BID Body Weight <60 kg: • 30 mg BID Peripheral neuropathy Lipoatrophy Pancreatitis Lactic acidosis/severe hepatomegaly with hepatic steatosis Hyperlipidemia Insulin resistance/diabetes mellitus Rapidly progressive ascending neuromuscular weakness
  • 23.
  • 24.
    Nevirapine (Viramune) In combination with otherantiretroviral agents for treatment of progressive HIV infection 200 mg/d × 14 days then 200 mg bid or 400 mg extended release qd Skin rash including SJS, hepatotoxicity Efavirenz (Sustiva) For treatment of HIV infection in combination with other antiretroviral agents 600 mg qhs Rash, dysphoria, elevated liver function tests, drowsiness, abnormal dreams, depression, lipid abnormalities, potentially teratogenic QT interval prolongation
  • 25.
    Etravirine (Intelence) In combination with otherantiretroviral agents in treatment- experienced patients whose HIV is resistant to non- nucleoside reverse transcriptase inhibitors and other anti- retroviral medications 200 mg bid Rash, SJS, nausea, hypersensitivity reactions Rilpivirine (Edurant) In combination with other drugs in previously untreated patients when treatment is indicated. 25 mg qd Nausea, dizziness, somnolence, vertigo, less CNS toxicity and rash than Efavirenz QT interval prolongation
  • 26.
  • 27.
    Lopinavir/ Ritonavir (LPV/r) Kaletra Incombination with other antiretroviral agents for treatment of HIV infection when treatment is warranted (LPV 400 mg + RTV 100 mg) BID, or (LPV 800 mg + RTV 200 mg) once daily Nausea, abdominal pain, hyperglycemia, fat redistribution, lipid abnormalities, may alter levels of many other drugs, paresthesias, hepatitis PR interval prolongation QT interval prolongation and torsades de pointes Atazanavir (Reyataz) For treatment of HIV infection in combination with other antiretroviral agents 400 mg qd or 300 mg qd + ritonavir 100 mg qd when given with efavirenz Hyperbilirubinemia, PR prolongation, nausea, vomiting, hyperglycemia, fat maldistribution, rash transaminase eleva- tions, renal stones Darunavir (Prezista) In combination with 100 mg ritonavir for combination therapy in treatment- experienced adults 600 mg + 100 mg ritonavir twice daily with food Diarrhea, nausea, headache, skin rash, hepatotoxicity, hyperlipidemia, hyperglycemia
  • 28.
    Fosamprenavi r (FPV) Lexiva (a prodrug of APV) InARV-Naive Patients: FPV 1400 mg BID, or (FPV 1400 mg + RTV 100–200 mg) once daily, or (FPV 700 mg + RTV 100 mg) BID Skin rash (12% to 19%): FPV has a sulfonamide moiety. Diarrhea, nausea, vomiting Headache Hyperlipidemia Serum transaminase elevation Hyperglycemia Fat maldistribution Possible increased bleeding episodes in patients with hemophilia Nephrolithiasis Saquinavir (SQV) Invirase (SQV 1000 mg + RTV 100 mg) BID GI intolerance, nausea, and diarrhea Headache Serum transaminase elevation Hyperlipidemia Hyperglycemia Fat maldistribution Possible increased bleeding episodes in patients with hemophilia PR interval prolongation QT interval prolongation. Torsades de pointes have been reported. Tipranavir (TPV) Aptivus (TPV 500 mg + RTV 200 mg) BID Hepatotoxicity ,Skin rash Rare cases of fatal and nonfatal intracranial hemorrhages have been reported.
  • 29.
    ■ Other Proteaseinhibitors are: ■ Indinavir (IDV) Crixivan ■ Nelfinavir (NFV) Viracept
  • 30.
  • 31.
    Enfuvirtide (Fuzeon) Incombination with other agents in treatment- experienced patients with evidence of HIV-1 replication despite ongoing anti- retroviral therapy 90 mg SC bid Local injection reactions, hypersensitivity reactions, increased rate of bacterial pneumonia Maraviroc (Selzentry) In combination with other antiretroviral agents in adults infected with only CCR5-tropic HIV-1 150–600 mg bid depending on con- comitant medica- tions Hepatotoxicity, nasopharyngitis, fever, cough, rash, abdominal pain, dizziness, musculo- skeletal symptoms Orthostatic hypotension, especially in patients with severe renal insufficiency
  • 32.
  • 33.
    Raltegravir (Isentress) In combination with otherantiretroviral agents 400 mg bid Nausea, headache, diarrhea, CPK elevation, muscle weakness, rhabdomyolysis depression Elvitegravir (Available only in com- bination with cobi- cistat, tenofovir, and emtricitabine [Stribild] Fixed-dose combination 1 tablet daily Diarrhea, nausea, upper respiratory infections, headache, depression. Dolutegravir (Tivicay) In combination with other antiretroviral agents 50 mg daily for treatment-naïve patients 50 mg twice daily for treatment- experienced patients or those also receiving efavirenz or rifampin Insomnia, headache, hyper- sensitivity reactions, hepato- toxicity, depression.
  • 34.
    Pharmacokinetic Enhancers (Boosters) ■ PKenhancing is a strategy used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. ■ Currently, two agents are used as PK enhancers: ritonavir (RTV) and cobicistat (COBI). Both of these drugs are potent inhibitors of the CYP3A4 enzyme, resulting in higher systemic exposures of the co-administered ARV metabolized by this pathway. Importantly, RTV and COBI have different effects on other CYP- or UGT-metabolizing enzymes and drug transporters. ■ Complex or unknown mechanisms of PK-based interactions preclude extrapolation of RTV drug interactions to certain COBI interactions, such as interactions with warfarin, phenytoin, voriconazole, oral contraceptives, and certain HMG-CoA reductase inhibitors (or statins).
  • 35.
    What Not toUse ■ Some antiretroviral (ARV) regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below. Antiretroviral Drugs Not Recommended: ■ The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: delavirdine (DLV), didanosine (ddI), indinavir (IDV), nelfinavir (NFV), and stavudine (d4T).
  • 36.
    Antiretroviral Regimens NotRecommended ■ Monotherapy ■ Nucleoside reverse transcriptase inhibitor (NRTI) monotherapy is inferior to dual-NRTI therapy. ■ Dual-NRTI Regimens These regimens are inferior to triple-drug combination regimens (AI). ■ Triple-NRTI Regimens Triple-NRTI regimens have suboptimal virologic activity or a lack of data (AI).
  • 37.
    Virologic Response Definitions ■Virologic suppression: A confirmed HIV RNA level below the LLOD of available assays. ■ Virologic failure: The inability to achieve or maintain suppression of viral replication to an HIV RNA level <200 copies/mL. ■ Incomplete virologic response: Two consecutive plasma HIV RNA levels ≥200 copies/mL after 24 weeks on an ARV regimen in a patient who has not yet had documented virologic suppression on this regimen. ■ Virologic rebound: Confirmed HIV RNA ≥200 copies/mL after virologic suppression. ■ Virologic blip: After virologic suppression, an isolated detectable HIV RNA level that is followed by a return to virologic suppression. ■ Low-level viremia: Confirmed detectable HIV RNA <200 copies/mL.
  • 38.
    Virologic Failure ■ Evaluationof virologic failure should include an assessment of adherence, drug-drug or drug-food interactions, drug tolerability, HIV RNA and CD4 T lymphocyte (CD4) cell count trends over time, ART history, and prior and current drug-resistance testing results. ■ Drug-resistance testing should be performed while the patient is taking the failing antiretroviral (ARV) regimen (AI) or within 4 weeks of treatment discontinuation (AII). Even if more than 4 weeks have elapsed since ARVs were discontinued, resistance testing can still provide useful information to guide therapy, although it may not detect previously selected resistance mutations (CIII). ■ The goal of treatment for ART-experienced patients with drug resistance who are experiencing virologic failure is to establish virologic suppression (i.e. HIV RNA below the lower limits of detection of currently used assays) (AI).
  • 39.
    ■ A newregimen should include at least two, and preferably three, fully active agents (AI). A fully active agent is one that is expected to have uncompromised activity on the basis of the patient’s ART history and his or her current and past drug-resistance testing results. A fully active agent may also have a novel mechanism of action. ■ In general, adding a single ARV agent to a virologically failing regimen is not recommended because this may risk the development of resistance to all drugs in the regimen (BII). ■ For some highly ART-experienced patients with extensive drug resistance, maximal virologic suppression may not be possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and delay clinical progression.
  • 40.
    ■ When itis not possible to construct a viable suppressive regimen for a patient with multidrug resistant HIV, the clinician should consider enrolling the patient in a clinical trial of investigational agents or contacting pharmaceutical companies that may have investigational agents available. ■ When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs active against HBV should be continued as part of the new regimen. Discontinuation of these drugs may cause serious hepatocellular damage resulting from reactivation of HBV. ■ Discontinuing or briefly interrupting therapy may lead to a rapid increase in HIV RNA, a decrease in CD4 cell count, and an increase in the risk of clinical progression. Therefore, this strategy is not recommended in the setting of virologic failure (AI).
  • 41.
    Regimen Switching inthe Setting of Virologic Suppression ■ As with ART-naive patients, the use of a three-drug combination regimen is generally recommended when switching patients with suppressed viral loads to a new regimen. However, there is growing evidence that certain two-drug regimens can maintain virologic suppression. ■ Monotherapy with either a boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI) has been explored in several trials or cohort studies, and has been associated with an unacceptable rate of virologic failure and the development of resistance; therefore, monotherapy as a switching strategy is not recommended (AII). ■ More intensive monitoring to assess tolerability, viral suppression, adherence, and laboratory changes is recommended during the rst 3 months after a regimen switch (AIII).
  • 42.
    ■ Within-class switchesprompted by adverse events or the availability of ARVs within the same class that offer a better safety profile, reduced dosing frequency, or lower pill burden usually maintain viral suppression, provided there is no drug resistance to the new ARV. Some examples of within-class switch strategies are switching from efavirenz (EFV) to rilpivirine (RPV), from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) etc ■ Between-class switches generally maintain viral suppression, provided there is no resistance to the other components of the regimen. Some examples of between- class switch strategies are replacing a boosted PI with RPV, or replacing an NNRTI or a boosted PI with an INSTI or maraviroc (MVC). ■ When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs active against HBV infection should be continued as part of the new regimen. Discontinuation of these drugs may cause serious hepatocellular damage resulting from reactivation
  • 43.
    Considerations for Antiretroviral Usein Special Patient Populations
  • 44.
    Acute and Recent(Early) HIV Infection ■ Acute HIV-1 infection, the phase of HIV-1 disease immediately after infection, is typically characterized by an initial burst of viremia; although anti-HIV-1 antibodies are undetectable, HIV-1 RNA or p24 antigen is present. Recent infection is generally considered the phase up to 6 months after infection during which detectable anti-HIV-1 antibodies develop. ■ Although some patients with acute HIV-1 infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, and other symptoms, Primary care clinicians may fail to recognize acute HIV-1 infection because its manifestations are often similar to those of many other viral infections, such as influenza and infectious mononucleosis. Acute infection can also be asymptomatic.
  • 45.
    ■ Antiretroviral therapy(ART) is recommended for all individuals with HIV-1 infection (AI) including those with early HIV-1 infection. ■ Once initiated, the goal of ART is to suppress plasma HIV- 1 RNA to undetectable levels (AIII). Testing for plasma HIV-1 RNA levels, CD4 T lymphocyte counts, and toxicity monitoring should be performed as recommended for patients with chronic HIV-1 infection (AII). ■ Genotypic drug resistance testing should be performed before initiation of ART to guide the selection of the regimen (AII). ■ ART can be initiated before drug resistance test results are available. Because resistance to pharmacokinetically enhanced protease inhibitors (PIs) emerges slowly and clinically significant transmitted resistance to PIs is uncommon, a boosted darunavir (DRV) and emtricitabine (FTC) plus either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) are recommended regimens in this setting (AIII).
  • 46.
    ■ When resultsof drug resistance testing are available, the treatment regimen can be modified if warranted (AII). In patients without transmitted drug resistant virus, therapy should be initiated with one of the combination regimens that is recommended for patients with chronic HIV-1 infection (AIII). ■ Patients starting ART should be willing and able to commit to treatment and should understand the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may recommend that patients defer therapy because of clinical or psychosocial factors.
  • 47.
    Adolescents and YoungAdults with HIV ■ Adolescents living with HIV largely belong to two distinct groups—those who acquired HIV in infancy, and are heavily antiretroviral therapy (ART)-experienced, and those who acquired HIV more recently during their teens. ■ ART is recommended for all individuals with HIV (AI) to reduce morbidity and mortality. Thus, ART is also recommended for ART-naive adolescents. However, before initiation of therapy, adolescents’ readiness and ability to adhere to therapy within their psychosocial context need to be carefully considered as part of therapeutic decision making (AIII). ■ Once ART is initiated, appropriate support is essential to reduce potential barriers to adherence and maximize the success in achieving sustained viral suppression (AII).
  • 48.
    ■ The adolescentsexual maturity rating can be helpful to guide regimen selection for initiation of or changes in ART as recommended by either these Adult and Adolescent ARV Guidelines or the Pediatric ARV Guidelines. ■ Pediatric and adolescent care providers should prepare adolescents for the transition into adult care settings. Adult providers should be sensitive to the challenges associated with such transitions, consulting and collaborating with adolescent HIV care providers to insure adolescents’ successful transition and continued engagement in care (AIII).
  • 49.
    Women with HIV ■Antiretroviral therapy (ART) is recommended for all women living with HIV to improve their health and to reduce the risk of HIV transmission to HIV-uninfected sex partners (AI). ■ In pregnant women, an additional goal of therapy is to maintain a viral load below the limit of detection throughout pregnancy to reduce the risk of transmission to the fetus and newborn (AI). ■ When selecting an antiretroviral (ARV) combination regimen for a pregnant woman, clinicians should consider the available safety, efficacy, and pharmacokinetic (PK) data on use during pregnancy for each agent. The risks and benefits of ARV use during pregnancy should be discussed with all women (AIII). ■ For women taking ARV drugs that have significant PK interactions with hormonal contraceptives, an alternative or additional effective contraceptive method to prevent unintended pregnancy is recommended (AIII). Switching to an ARV drug without interactions with hormonal contraceptives may also be considered (BIII).
  • 50.
    ■ Non-pregnant womenof childbearing potential should undergo pregnancy testing before initiation of efavirenz (EFV) and receive counselling about the potential risk to the fetus and desirability of avoiding conception while on EFV-based regimens (AIII). ■ Regimens that do not include EFV should be considered in women who are planning to become pregnant or are sexually active and not using effective contraception (BIII). ■ Women on a suppressive regimen containing EFV who become pregnant and present to antenatal care during the first trimester can continue EFV throughout pregnancy (CIII).
  • 51.
    Preferred Two-NRTI Backbones ABC/3TCAvailable as FDC. Can be administered once daily. ABC should not be used in patients who test positive for HLA-B*5701 because of risk of hypersensitivity reaction. ABC/3TC with ATV/r or with EFV is not recommended if pretreatment HIV RNA is >100,000 copies/mL. TDF/FTC or TDF/3TC TDF/FTC available as FDC. Either TDF/FTC (coformulated) or TDF with separate 3TC can be administered once daily. Preferred PI Regimens ATV/r plus a Preferred Two-NRTI Backbone Once-daily administration. Extensive experience in pregnancy. Maternal hyperbilirubinemia; no clinically significant neonatal hyperbilirubinemia or kernicterus reported, but neonatal bilirubin monitoring recommended. DRV/r plus a Preferred Two-NRTI Backbone Better tolerated than LPV/r. PK data available. Increasing experience with use in pregnancy. Must be used twice daily in pregnancy. Preferred Integrase Inhibitor Regimen(s) RAL plus a Preferred Two-NRTI Backbone PK data available and increasing experience in pregnancy. Rapid viral load reduction (potential role for women who present for initial therapy late in pregnancy). Twice-daily dosing required.
  • 52.
    Stopping Antiretroviral DrugsDuring Pregnancy ■ Discontinuation of antiretroviral (ARV) drug regimens during pregnancy may be indicated in some situations, including serious drug-related toxicity, pregnancy-induced hyperemesis unresponsive to anti-emetics, or acute illnesses or planned surgeries that preclude oral intake ■ If an ARV drug regimen must be stopped for any reason, all ARV drugs should be stopped simultaneously and ARV therapy should then be reinitiated simultaneously as soon as possible, whether restarting the same regimen or a new regimen. ■ Continuation of all drugs during the intrapartum period generally is recommended. Women who are having elective cesarean delivery can take oral medications before the procedure and restart drugs following surgery. Because most drugs are given once or twice daily, it is likely that no doses would be missed or that at most, the postpartum dose would be given a few hours late.
  • 53.
    HIV-2 Infection ■ Comparedto HIV-1 infection, the clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma HIV-2 RNA levels, and lower mortality; however, progression to AIDS does occur. ■ There have been no randomized trials addressing the question of when to start antiretroviral therapy (ART) or the choice of initial or second-line therapy for HIV-2 infection; thus, the optimal treatment strategy has not been de ned. ■ Although the optimal CD4 T lymphocyte (CD4) cell count threshold for initiating ART in HIV-2 infection is unknown, therapy should be started before there is clinical progression. ■ HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and to enfuvirtide; thus, these drugs should not be included in an antiretroviral regimen for a patient living with HIV-2 infection.
  • 54.
    ■ Pending moredefinitive data on outcomes in an ART-naive patient who has HIV-2 mono-infection or HIV-1/HIV-2 dual infection and requires treatment, an initial antiretroviral therapy regimen for these patients should include two nucleoside reverse transcriptase inhibitors plus an HIV-2 active boosted protease inhibitor or integrase strand transfer inhibitors. ■ Monitoring of HIV-2 RNA levels, CD4 cell counts, and clinical improvements can be used to assess treatment response, as is recommended for HIV-1 infection. ■ Resistance-associated viral mutations to nucleoside reverse transcriptase inhibitors, protease inhibitors, and/or integrase strand transfer inhibitors may develop in patients with HIV-2 while on therapy. However, no validated HIV-2 genotypic or phenotypic antiretroviral resistance assays are available for clinical use. ■ In the event of virologic, immunologic, or clinical failure, second-line treatment should be instituted in consultation with an expert in HIV-2 management.
  • 55.
    HIV and theOlder Patient ■ Antiretroviral therapy (ART) is recommended for all patients regardless of CD4 T lymphocyte cell count (AI). ART is especially important for older patients because they have a greater risk of serious non-AIDS complications and potentially a blunted immunologic response to ART. ■ Adverse drug events from ART and concomitant drugs may occur more frequently in older patients living with HIV than in younger patients with HIV. Therefore, the bone, kidney, metabolic, cardiovascular, and liver health of older patients should be monitored closely.
  • 56.
    ■ Polypharmacy iscommon in older patients with HIV; therefore, there is a greater risk of drug-drug interactions between antiretroviral drugs and concomitant medications. Potential for drug-drug interactions should be assessed regularly, especially when starting or switching ART and concomitant medications. ■ HIV experts, primary care providers, and other specialists should work together to optimize the medical care of older patients with HIV with complex comorbidities. ■ Early diagnosis of HIV and counselling to prevent secondary transmission of HIV remains an important aspect of the care of the older patient with HIV.
  • 57.
    Hepatitis B/HIV VirusCoinfection ■ Before initiation of antiretroviral therapy (ART), all patients who test positive for hepatitis B surface antigen (HBsAg) should be tested for hepatitis B virus (HBV) DNA using a quantitative assay to determine the level of HBV replication (AIII). ■ Because emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) have activity against both HIV and HBV, an ART regimen for patients with both HIV and HBV should be include (TAF or TDF) plus (3TC or FTC) as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral (ARV) regimen (AI).
  • 58.
    ■ If TDFor TAF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive ARV regimen (BI). Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. ■ Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when given to patients with HBV/HIV-coinfection (AII). Peg-interferon alfa monotherapy may also be considered in certain patients (CII). ■ Other HBV treatment regimens, including adefovir alone or in combination with 3TC or FTC and telbivudine, are not recommended for patients with HBV/HIV coinfection (CII).
  • 59.
    ■ Discontinuation ofagents with anti-HBV activity may cause serious hepatocellular damage resulting from reactivation of HBV; patients should be advised against stopping these medications and be carefully monitored during interruptions in HBV treatment (AII). ■ If ART needs to be modified due to HIV virologic failure and the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII). ■ • HBV reactivation has been observed in persons with HBV infection during interferon-free HCV treatment. For that reason, all patients initiating HCV therapy should be tested for HBV. Persons with HCV/HIV coinfection and active HBV infection (determined by a positive HBsAg test) should receive ART that includes two agents with anti-HBV activity prior to initiating HCV therapy (AIII).
  • 60.
    Hepatitis C Virus/HIVCoinfection ■ All people with HIV should be screened for hepatitis C virus (HCV) infection (AIII). Patients at high risk of HCV infection should be screened annually and whenever incident HCV infection is suspected (AIII). ■ Antiretroviral therapy (ART) may slow the progression of liver disease by preserving or restoring immune function and reducing HIV- related immune activation and inflammation. For most persons with HCV/HIV coinfection, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be initiated in all patients with HCV/HIV coinfection, regardless of CD4 T lymphocyte (CD4) cell count (AI). ■ Initial ART regimens recommended for most patients with HCV/HIV coinfection are the same as those recommended for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, the ART and HCV treatment regimen should be selected with special consideration for potential drug-drug interactions and overlapping toxicities.
  • 61.
    ■ In patientswith lower CD4 counts (e.g., <200 cells/mm3), ART should be initiated promptly (AI) and HCV therapy may be delayed until the patient is stable on HIV treatment (CIII). ■ All patients with HCV/HIV coinfection should be evaluated for HCV therapy and have their liver fibrosis stage assessed to inform the length of their therapy, ribavirin need (a concern with some regimens), and subsequent risk of hepatocellular carcinoma and liver disease complications. ■ Persons with chronic HCV/HIV coinfection should be screened for active and prior hepatitis B virus (HBV) infection by testing for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B surface (HBsAb) and core (HBcAb total or IgG). Persons who are not immune to HBV infection (HBsAb-negative) should receive anti-HBV vaccination (AIII). ■ HBV reactivation has been observed in persons with HBV infection during interferon-free HCV treatment. Accordingly, persons with HCV/HIV coinfection and active HBV infection (HBsAg-positive) should receive ART that includes two agents with anti-HBV activity prior to initiating
  • 62.
    Tuberculosis/HIV Coinfection ■ Selectionof a tuberculosis (TB)-preventive treatment for individuals living with HIV and coinfected with latent tuberculosis infection (LTBI) should be based on the individual’s antiretroviral therapy (ART) regimen as noted below: – Any ART regimen can be used when isoniazid alone is used for LTBI treatment (AII). – Only efavirenz (EFV)- or raltegravir (RAL)-based regimens (in combination with either abacavir/lamivudine [ABC/3TC] or tenofovir – disoproxil fumarate/emtricitabine [TDF/FTC]) can be used with once-weekly isoniazid plus rifapentine (AIII). – If rifampin or rifabutin is used to treat LTBI, clinicians should review Tables 18a through 18e to assess the potential for interactions – among different antiretroviral (ARV) drugs and the rifamycins (BIII).
  • 63.
    ■ All patientswith both HIV and active TB who are not on ART should be started on ART as described below: • In patients with CD4 counts <50 cells/mm3: Initiate ART as soon as possible, but within 2 weeks of starting TB treatment (AI). • In patients with CD4 counts ≥50 cells/mm3: Initiate ART within 8 weeks of starting TB treatment (AIII). • In all pregnant women with HIV: Initiate ART as early as feasible, for treatment of maternal HIV infection and to prevent mother- to-child transmission (MTCT) of HIV (AIII). • In patients with tuberculous meningitis: Caution should be exercised when initiating ART early, as high rates of adverse events and deaths have been reported in a randomized trial (AI). ■ Rifamycins are critical components of TB treatment regimens and should be included for patients with both HIV and active TB, unless precluded because of TB resistance or toxicity. However, rifamycins have a considerable potential for drug- drug interactions.
  • 64.
    Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome ■IRIS is a clinical condition caused by ART-induced restoration of pathogen-specific immune responses to opportunistic infections such as TB, resulting in either the deterioration of a treated infection (paradoxical IRIS) or a new presentation of a previously subclinical infection (unmasking IRIS). ■ TB-associated IRIS (TB- IRIS) has been reported in 8% to more than 40% of patients starting ART after TB is diagnosed, although the incidence depends on the definition of IRIS and the intensity of monitoring. ■ Predictors of IRIS include a baseline CD4 count <50 cells/mm3; higher on-ART CD4 counts; high pre-ART and lower on-ART HIV viral loads; severity of TB disease, especially high pathogen burden; and a less than 30-day interval between initiation of TB and HIV treatments. Most IRIS in HIV/TB disease occurs within 3 months of the start of ART.
  • 65.
    ■ Manifestations ofunmasking TB-IRIS are characterized by their marked inflammatory nature, such as high fever, respiratory distress, lymphadenitis, abscesses, and sepsis syndrome. Manifestations of paradoxical TB-IRIS include fevers, new or worsening lymphadenopathy, new or worsening pulmonary infiltrates, enlarging pleural effusions, and new or enlarging tuberculomas. ■ IRIS ranges from mild to severe to life-threatening. Patients with mild or moderately severe IRIS can be managed symptomatically or treated with nonsteroidal inflammatory agents. ■ Patients with more severe IRIS can be treated successfully with corticosteroids, although data on the optimal dose, duration of therapy, and overall safety and efficacy are limited. In the presence of IRIS, neither TB therapy nor ART should be stopped because both therapies are necessary for the long-term health of the patient (AIII).
  • 66.
    Acute Opportunistic Infections andMalignancies ■ In patients who have AIDS-associated opportunistic diseases for which there is no effective therapy (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy), improvement of immune function with ART may improve disease outcomes, thus ART should be started as soon as possible. ■ For patients with mild to moderate cutaneous Kaposi’s sarcoma (KS), prompt initiation of ART alone without chemotherapy has been associated with improvement of the KS lesions, even though initial transient progression of KS lesions as a manifestation of immune reconstitution inflammatory syndrome (IRIS) can also occur. ■ Similarly, although an IRIS-like presentation of non-Hodgkin’s lymphoma after initiation of ART has been described, greater ART-mediated viral suppression is also associated with longer survival among individuals undergoing treatment for AIDS lymphoma.
  • 67.
    ■ In thesetting of some OIs, such as cryptococcal and tuberculous meningitis, for which immediate ART may increase the risk of serious IRIS, a short delay before initiating ART may be warranted. ■ When ART is initiated in a patient with an intracranial infection, the patient should be closely monitored for signs and symptoms associated with IRIS. In the setting of other OIs, such as Pneumocystis jirovecii pneumonia, early initiation of ART is associated with increased survival; therefore, ART should not be delayed. ■ In patients who have active non-meningeal tuberculosis, initiating ART during treatment for tuberculosis confers a significant survival advantage; therefore, ART should be initiated
  • 68.
    Plasma HIV-1 RNA(Viral Load) and CD4 Count Monitoring ■ Viral load is the most important indicator of initial and sustained response to ART (AI) and should be measured in all patients with HIV at entry into care (AIII), at initiation of therapy (AIII), and on a regular basis thereafter. For those patients who choose to delay therapy, repeat viral load testing while not on ART is optional (CIII). ■ The minimal change in viral load considered to be statistically significant (2 standard deviations) is a three- fold change (equivalent to a 0.5 log10 copies/mL change). ■ Optimal viral suppression is defined generally as a viral load persistently below the level of detection (HIV RNA <20 to 75 copies/mL, depending on the assay used). However, isolated blips (viral loads transiently detectable at low levels, typically HIV RNA <400 copies/mL) are not uncommon in successfully treated patients and are not predictive of virologic failure.
  • 69.
    ■ The CD4count is used to assess a patient’s immunologic response to ART. It is also used to determine whether prophylaxis for OIs can be discontinued. ■ For most patients on therapy, an adequate response is defined as an increase in CD4 count in the range of 50 to 150 cells/mm3 during the first year of ART, generally with an accelerated response in the first 3 months of treatment. ■ Subsequent increases average approximately 50 to 100 cells/mm3 per year until a steady state level is reached. ■ Patients who initiate therapy with a low CD4 countor at an older age may have a blunted increase in their counts despite virologic suppression.
  • 70.
    Recommendations on theIndications and Frequency of Viral Load and CD4 Count Monitoring
  • 71.
    Poor CD4 CellRecovery and Persistent Inflammation Despite Viral Suppression ■ Morbidity and mortality from several AIDS and non-AIDS conditions are increased in individuals with HIV despite antiretroviral therapy (ART)-mediated viral suppression, and are predicted by persistently low CD4 T lymphocyte (CD4) cell counts and/or persistent immune activation. ■ ART intensification by adding antiretroviral (ARV) drugs to a suppressive ART regimen does not consistently improve CD4 cell recovery or reduce immune activation and is not recommended (AI). ■ Monitoring markers of immune activation and inflammation is not recommended because no immunologically targeted intervention has proven to improve the health of individuals with abnormally high biomarker levels, and many markers that predict morbidity and mortality fluctuate widely in individuals (AII). ■ Because there are no proven interventions to improve CD4 cell recovery and/or inflammation, efforts should focus on addressing modifiable risk factors for chronic disease (e.g., encouraging smoking cessation, a healthy diet, and exercise; treating hypertension and hyperlipidemia) (AII).
  • 72.
    Treatment Goals ■ Afterinitiation of effective ART, viral load reduction to below limits of assay detection usually occurs within the first 12 to 24 weeks of therapy. Predictors of virologic success include the following: – Low baseline viremia; – High potency of the ARV regimen; – Tolerability of the regimen; – Convenience of the regimen; and – Excellent adherence to the regimen.
  • 73.
    Post -Exposure prophylaxis ■A 28-day course of nPEP is recommended for HIV- uninfected persons who seek care ≤ 72 hours after a non- occupational exposure to blood, genital secretions, or other potentially infected body fluids of persons known to be HIV infected or of unknown HIV status when that exposure represents a substantial risk for HIV acquisition. ■ Adults and adolescents aged ≥ 13 years, including pregnant women, with normal renal function (creat CL ≥ 60 mL/min) ■ A 3-drug regimen consisting of tenofovir DF 300 mg and fixed dose combination emtricitabine 200 mg (Truvadac) once daily with raltegravir 400 mg twice daily or dolutegravir 50 mg once daily ■ If CrCL ≤59 mL/min, A 3-drug regimen consisting of zidovudine and lamivudine, with both doses adjusted to degree of renal function with raltegravir 400 mg twice daily or dolutegravir 50 mg once daily.
  • 74.
    References ■ Guidelines forthe Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. (March 2018) [Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) ] ■ 19th edition of Harrison’s Principles of Internal Medicine.