REVIEW URRENT C OPINION
HIV: new drugs, new guidelines Anna Maria Geretti and Maria Tsakiroglou
Purpose of review This review discusses recent changes in HIV treatment guidelines, focussing on the optimal time for starting antiretroviral therapy (ART) in chronic asymptomatic infection, and treatment options for ART-naı¨ve patients. Recent findings Understanding of HIV pathogenesis has progressed significantly, with a growing appreciation of the role of HIV replication in causing inflammation and promoting both AIDS and non-AIDS diseases. Early suppression of HIV replication with ART benefits the individual, and by reducing transmission and promoting engagement with care also brings public health benefits. For years, efavirenz-based ART was favoured by treatment guidelines, reflecting unsurpassed performance in clinical trials. New treatment options show high efficacy and safety and include single-tablet coformulations for once-daily dosing to improve convenience. Recent data have demonstrated superiority over efavirenz of regimens based on rilpivirine in patients with low pre-ART HIV-1 RNA load and raltegravir or dolutegravir regardless of the viral load. Summary Some guidelines now recommend starting ART regardless of CD4 cell counts, whereas others take a more cautious approach pending results from studies that are testing the clinical benefit of early therapy. New treatment options allow therapy to be tailored to the patient’s circumstances and are suitable for early ART initiation. Keywords antiretroviral therapy, CD4 count, clinical trials, guidelines
INTRODUCTION
that the effect may persist after starting ART [2,3 ,4 ]. At the same time, efforts to develop an HIV cure have highlighted the importance of preserving – rather than restoring – immune function, which is more likely if ART is initiated earlier rather than later [5 ]. These factors provide a strong rational for the concept that suppression of HIV replication offsets any potential negative effects of treatment even at high CD4 cell counts. Data indicating a clinical benefit of early ART come from observational cohorts and secondary analyses of clinical trials, and there remains a paucity of controlled studies designed to address the question. Evidence favours starting ART when the CD4 count is between 350 and 500 cells/ml compared with &
The incidence of AIDS-defining disease is low when CD4 counts are greater than 350 cells/ml and for many years, the potential benefits of starting antiretroviral therapy (ART) earlier had to be balanced against the potential risks of life-long treatment, primarily drug toxicity, and lapses in adherence leading to drug resistance and exhaustion of treatment options. Major advances in our understanding of HIV pathogenesis, and the introduction of well tolerated, effective, and convenient treatment options, are gradually shifting opinions (Table 1).
STARTING ANTIRETROVIRAL THERAPY IN CHRONIC ASYMPTOMATIC HIV INFECTION Observational cohorts show a small, but persistent, risk of AIDS-defining disease – especially malignancies – at CD4 counts of 500–749 cells/ml relative to patients with higher counts [1 ]. There has been growing appreciation that HIV replication, by inducing chronic T-cells activation and inflammation, also increases the incidence of non-AIDS illnesses (for example, cardiovascular disease), and &
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Department of Clinical Infection, Microbiology & Immunology, Institute of Infection & Global Health, University of Liverpool, Liverpool, UK Correspondence to Professor Anna Maria Geretti, MD, PhD, Department of Clinical Infection, Microbiology & Immunology, Institute of Infection & Global Health, University of Liverpool, 8 West Derby Street, Liverpool L69 7BE, UK. Tel: +44 151 795 9665; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:545–553 DOI:10.1097/QCO.0000000000000106
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Antimicrobials
KEY POINTS The goals of ART are to reduce HIV-related disease, impact of comorbidities, and risk of HIV transmission. Advances in our understanding of HIV pathogenesis provide a strong rational for early treatment initiation. HIV treatment has made dramatic advances in the last two decades. Some new drugs show higher efficacy – predominantly through improved safety and tolerability – than the efavirenz-based standard of care. Most regimens for first-line therapy have features that make them less suitable for certain patient groups. The recently approved integrase inhibitor dolutegravir – now also available in single-tablet coformulation with abacavir and lamivudine – offers excellent efficacy, safety and tolerability, a high genetic barrier to resistance, once-daily dosing without food requirements, and moderate potential for drug–drug interactions. Clinical experience remains limited. Cost–benefit analyses will test new treatments against older options that are now becoming available as generics, including efavirenz and lamivudine.
starting when the CD4 count is well below 350 cells/ml [6 ]; the benefit of starting ART at a CD4 count greater than 500 cells/ml is unclear. The Strategic Timing of Antiretroviral Treatment study is a randomized trial that will use a composite primary end-point of AIDS diagnoses, serious non-AIDS diagnoses, and all-cause mortality to compare immediate versus delayed ART in patients with CD4 counts
greater than 500 cells/ml. The trial is expected to report in 2016. There is unequivocal evidence that in HIVdiscordant couples, treatment of the positive partner significantly lowers the probability of transmission to the uninfected partner [7]. Increasing ART coverage also affects a substantial decline in HIV incidence at the population level. In challenging, high-prevalence settings in sub-Saharan Africa, HIV-uninfected individuals living in a community with ART coverage of 30–40% are 38% less likely to acquire HIV than someone living in a community in which ART coverage is less than 10% [8 ]. These considerations have brought important changes in treatment guidelines, and some panels have expressed the consensus that a ‘test and treat’ approach should be favoured, whereby ART is started regardless of the CD4 cell count (Table 2) [9,10]. Some experts advocate a more cautious approach and emphasize that the decision to start treatment when the CD4 count is greater than 350 cells/ml must consider available resources, local programmatic needs, and the patient’s circumstances (Table 3), taking into account age, comorbidities, transmission risk, and the individual’s preference [11–13]. &&
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EFAVIRENZ FOR THE INITIAL TREATMENT OF HIV INFECTION The combination of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz with two nucleoside or nucleotide reverse transcriptase
Table 1. Considerations in favour of early initiation of antiretroviral therapy Factor
Mechanism
Outcome
Virus
Ongoing replication
Immunodeficiency and opportunistic disease Chronic T-cell activation and inflammation causes immunosenescence and accelerated ageing of systems and functions (e.g., cardiovascular, kidney, liver, and neurocognitive) Increased risk of malignancies Accelerated progression of chronic viral hepatitis Increased risk of transmission High viral reservoirs and impaired immune function reduce the likelihood of success of potential curative strategies
Treatment
New drugs
Improved efficacy reduces the risk of failure and drug resistance Improved tolerability facilitates adherence Improved safety reduces long-term toxicity
Coformulations Patient
546
Reduced pill burden and dosing frequency improve convenience
Ageing
Older patients are at increased risk of both AIDS and non-AIDS morbidities
Long-term survival
Unmasking of comorbidities (e.g., cardiovascular, renal, and bone disease); impact of coinfections (e.g., chronic viral hepatitis)
Engagement
Treatment promotes retention into care
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HIV: new drugs, new guidelines Geretti and Tsakiroglou Table 2. CD4 cell count cut-offs for starting antiretroviral therapy in chronic asymptomatic HIV infectiona CD4 count Guideline
350–500 (cells/ml)
>500 (cells/ml)
IAS, USA, July 2014b
Offer (A1a)
Offer (BIII)
DHHS, USA, May 2014c
Offer (AII)
Offer (BIII)
WHO, July 2014
Offer
Offer if HBV with severe liver disease; active TB; HIV serodiscordant couple; or for programmatic and operational reasons, particularly in generalized epidemics
EACS, Europe, June 2014
Consider
Consider
Offer if HBV or HCV
Offer if HBV requiring treatment
Offer at any CD4 count if non-AIDS HIV-related disease (kidney disease, NC impairment, HL, HPV-associated cancers) Consider at any CD4 count in order to reduce transmission BHIVA, UK, November 2013d
Offer if HBV (1B) or HCV (1C)
Offer if HBV requiring treatment (2B)
Offer at any CD4 count if non-AIDS HIV-related disease (kidney disease, ITP, NC impairment); malignancy requiring immunosuppressive radiotherapy/chemotherapy (1C); or patient wishes to reduce risk of transmission to partners (GPP) BHIVA, British HIV Association; DHSS, Department of Health & Social Security; EACS, European AIDS Clinical Society; HBV, hepatitis B virus; HCV, hepatitis C virus; HL, Hodgkin’s lymphoma; HPV, human papilloma virus; IAS, International Antiviral Society; ITP, idiopathic thrombocytopenic purpura; NC, neurocognitive; TB, tuberculosis. a All guidelines recommend treatment at a CD4 count less than 350 cells/ml. b Strength of recommendation: A ¼ strong; B ¼ moderate. Quality of evidence: Ia ¼ at least one randomized clinical trial published in peer-reviewed literature; III ¼ panel’s analysis of available evidence. c Strength of recommendation: A ¼ strong; B ¼ moderate. Quality of evidence: II ¼ data from well designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III ¼ expert opinion. d Strength of recommendation: 1 ¼ strong; 2 ¼ moderate/optional. Quality of evidence: B ¼ moderate (randomized trials that suffer from limitations, or observational studies with consistent effects and exclusion of most potential sources of bias); C ¼ low (controlled trials with several very serious limitations or observational studies with limited evidence on effects and exclusion of most potential sources of bias); GPP ¼ good practice points, on the basis of expert opinion.
Table 3. Factors that guide initial treatment selection in HIV care Virus
Transmitted drug-resistance Pretreatment HIV-1 RNA load
Treatment
Safety profile Convenience of dosing Food requirements Known or potential drug interactions Genetic barrier to resistance Cost
Patient
Adherence potential Comorbidties Employment and life style Personal preferences Drug abuse or dependency HLA-B5701 status (for abacavir) Pretreatment CD4 cell count Pregnancy
inhibitors (NRTIs) – typically tenofovir and emtricitabine – has long served as the reference standard of care in clinical trials of first-line ART and has been a recommended option in treatment guidelines (Table 4). The preference is based on a long-standing record of efficacy and safety, convenience of oncedaily dosing, availability of a single-tablet coformulation with tenofovir and emtricitabine (Atripla), and a long half-life that forgives the occasional missed dose. In head-to-head comparisons with efavirenz, several antiretrovirals have shown a reduced incidence of side-effects that are typically associated with efavirenz use – primarily central nervous system (CNS) disturbances, skin rashes, and dyslipidaemia. Until recently, however, efavirenz-based ART remained unsurpassed in randomized trials using rates of HIV-1 RNA suppression and incidence and severity of adverse events as surrogate marker endpoints for clinical efficacy. The preferred use of efavirenz has been called into question (reviewed in [14]). To minimize the
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Antimicrobials Table 4. Preferred regimens for the initial treatment of HIV infection in Europe and North Americaa Guideline
NRTI backbone
Third agent
IAS, USA, July 2014
TDF/FTC
NNRTI: EFV, RPVb INI: DTG, EVG/cc, RAL PI: ATVþr, DRVþr
ABCd/3TC
NNRTI: EFVb INI: DTG PI: ATVþrb
DHHS, USA, May 2014
TDF/FTC or TDF þ 3TC
NNRTI: EFV, RPVb,e INI: DTG, EVG/cc, RAL PI: ATVþr, DRVþr
ABCd/3TC or ABCd þ FTC
TDF/FTC or ABCd/3TC
TDF/FTC
NNRTI: EFV, RPVb c
INI: EVG/c , RAL NNRTI: EFV INI: EVG/cc, RAL PI: ATVþr, DRVþr
3TC, lamivudine; ABC, abacavir; ATVþr, ritonavir-boosted atazanavir; DRVþr, ritonavir-boosted darunavir; DTG, dolutegravir; EFV, rfavirenz; EVG/ c, elvitegravir/cocibistat; FTC, emtricitabine; INI, integrase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside or nucleotide reverse transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir. a Regimens are listed by drug class and in alphabetical order. b Only if baseline plasma HIV-1 RNA load less than 100 000 copies/ml. c Only if pre-ART creatinine clearance greater than 70 ml/min. d Only if HLA-B5701 negative: some guidelines recommend caution with abacavir in patients with high risk for cardiovascular disease because of a proposed link between the drug and myocardial infarction; the link remains controversial. e Only if baseline CD4 count greater than 200 cells/ml.
impact of CNS side-effects, dosing must take place at night on an empty stomach (food increases absorption), which is not always convenient. There is a possible increase in neural tube defects in new-borns of mothers exposed to efavirenz during early pregnancy, renewing concerns about use in women of childbearing potential. Furthermore, although some of the typical neuropsychiatric side-effects (for example, dizziness and abnormal dreams) are often self-limited and not a frequent cause of discontinuation, there is growing awareness of long-term CNS disturbances, including a possible increased tendency to commit suicide in efavirenz recipients. Although the long half-life of efavirenz offers forgiveness, the shorter half-life of accompanying NRTIs can result in a period of inadvertent monotherapy if all treatment is stopped simultaneously, resulting in the selection of NNRTI resistance [15]. A single mutation in reverse transcriptase – typically K103N – is 548
New treatment options show improved safety and tolerability relative to efavirenz, while preserving virological and immunological efficacy. Several are available as single tablets for once-daily dosing, thus improving convenience and facilitating longterm adherence (reviewed in [17,18 ]). &
TENOFOVIR/EMTRICITABINE/RILPIVIRINE (COMPLERA OR EVIPLERA)
INI: DTG
PI: ATVþr, DRVþr BHIVA, UK, Nov 2013
NEW OPTIONS FOR THE INITIAL TREATMENT OF HIV INFECTION
NNRTI: EFVb PI: ATVþrb
EACS, Europe, June 2014
sufficient to abrogate the activity of efavirenz, which makes efavirenz vulnerable to both treatmentemergent and transmitted drug resistance [16].
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The STaR study was the first randomized trial in which all patients (n ¼ 786) took a single-tablet once-daily regimen without additional placebo, comprising either tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV) or tenofovir/emtricitabine/ efavirenz (TDF/FTC/EFV). Among patients with pre-ART viral load of less than 100 000 copies/ml, the response rates (RR) at week 48 were significantly higher in rilpivirine recipients, reflecting greater safety and tolerability and fewer discontinuations for adverse events [19 ]. In patients with a pre-ART viral load of greater than 100 000 copies/ml, higher rates of discontinuation due to adverse events in the TDF/FTC/EFV arm were balanced by higher rates of virological failure in the TDF/FTC/RPV arm, with resulting noninferiority. Similar findings were reported from the ECHO and THRIVE trials of coformulated tenofovir/emtricitabine (TDF/FTC) plus rilpivirine or efavirenz [20]. Thus, within the NNRTI class, rilpivirine offers a valid alternative to efavirenz for patients with favourable pre-ART parameters. Reduced CNS toxicity allows dosing at any time; however, for optimal absorption, rilpivirine must be taken with a solid meal and cannot be taken with proton-pump inhibitors. There is otherwise a low potential for drug–drug interactions. Rilpivirine is a weak inhibitor of the renal tubular transporter OCT2 (organic cation transporter 2) and in the first weeks of therapy causes a small and nonprogressive increase in serum creatinine concentration, which translates into reduced creatinine clearance and estimated glomerular filtration rate (eGFR). No renal safety concerns have emerged from clinical trials. Rilpivirine has less potential for causing dyslipidaemia than both efavirenz [19 ,21 ] and protease inhibitors [22 ]. In a randomized study, switching from a ritonavir-boosted protease inhibitor (PI/r, predominantly atazanavir, lopinavir, or darunavir) &
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HIV: new drugs, new guidelines Geretti and Tsakiroglou
plus two NRTIs (predominantly TDF/FTC) to TDF/ FTC/RPV maintained virological suppression over 48 weeks and significantly improved total cholesterol, low-density lipoprotein, and triglycerides [22 ]. Eligibility criteria were viral load suppression for at least 6 months, lack of previous NNRTI experience, and anticipated full activity of the NRTI backbone. Rilpivirine has a low genetic barrier to resistance, which makes TDF/FTC/RPV unsuitable for patients who may harbour resistance to any of its components. Among patients experiencing virological failure in clinical trials, treatment-emergent resistance to at least one regimen component occurred more frequently with rilpivirine than with efavirenz, particularly at high pre-ART viral load [23]. At low viral load, rilpivirine recipients had a similar incidence of NNRTI resistance (predominantly involving reverse transcriptase positions E138 and Y181) as those on efavirenz, but higher incidence of NRTI resistance (predominantly M184I/V) [24]. Interactions between the E138 and M184 mutational pathways explain these observations [25]. &
TENOFOVIR/EMTRICITABINE/ ELVITEGRAVIR/COBICISTAT (STRIBILD) The integrase inhibitor elvitegravir is primarily metabolized in the liver and intestines via the cytochrome P450 isoenzyme 3A4 pathway and must be taken with the cytochrome P450 isoenzyme 3A4 inhibitor cobicistat (and food) to obtain effective concentrations [26]. There is a resulting high potential for drug–drug interactions (for example, with both rifampicin and rifabutin, precluding use during concomitant tuberculosis therapy). In clinical trials of first-line ART, tenofovir/emtricitabine/elvitegravir/cobicistat (TDF/FTC/EVG/c) was noninferior to both TDF/FTC/EFV (study 102; n ¼ 700) and TDF/FTC plus ritonavir-boosted atazanavir (study 103; n ¼ 708) at week 48, and high RR were maintained across all arms through 144 weeks [27,28]. Self-limiting nausea was the most commonly reported side-effect. In study 102, more TDF/FTC/EVG/c recipients experienced increases in serum creatinine than patients on TDF/FTC/ EFV. The increase occurred within the first 4 weeks of treatment and usually plateaued subsequently without further increases through week 144. Like ritonavir, cobicistat inhibits the renal tubular transporter MATE-1 (multidrug and toxin extrusion transporter 1), reducing creatinine secretion without affecting the actual GFR. However, several cases of renal tubular disease occurred in low-risk individuals exposed to TDF/FTC/EVG/c in clinical trials. Although cobicistat is not thought to affect the
elimination of tenofovir, an interaction cannot be excluded which may enhance the tubular toxicity of tenofovir [29 ,30,31 ]. Monitoring of renal function is recommended. TDF/FTC/EVG/c offers another valuable option for patients who need to switch ART to improve tolerability or convenience. The open-label STRA TEGY trials randomized patients receiving TDF/FTC plus either an NNRTI (78% efavirenz) or a PI/r (40% atazanavir and 40% darunavir) to continue the current ART regimen or to switch to TDF/FTC/EVG/c [32,33 ]. Eligibility criteria were a suppressed viral load for at least 6 months, no prior virological failure, expected full activity of the NRTI backbone, and eGFR at least 70 ml/min. After 48 weeks, TDF/FTC/ EVG/c (n ¼ 290) showed noninferiority relative to continuing the NNRTI (n ¼ 143), albeit with better CNS tolerability. Relative to the PI/r continuation arm (n ¼ 140), TDF/FTC/EVG/c (n ¼ 293) showed significantly higher RR, accompanied by a significant decline in triglycerides, and more nausea, but reduced diarrhoea and bloating. TDF/FTC/EVG/c is not an option for ART-experienced patients who may harbour resistance to any of its component. Elvitegravir has a low genetic barrier to resistance and both NRTI resistance and integrase inhibitor resistance occur at virological failure, with cross-resistance to raltegravir and, partially, to dolutegravir (reviewed in [34]). &
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RALTEGRAVIR Raltegravir is a well established treatment option for ART-naı¨ve patients, reflecting high efficacy and tolerability, and the added advantage of a low potential for drug–drug interactions. The double-blind STARTMRK trial randomized 566 ART-naı¨ve patients to TDF/FTC plus either raltegravir or efavirenz. The trial was originally planned for 96 weeks and then extended. At the 5-year study conclusion, RR were significantly higher in the raltegravir arm [35 ]. Although both regimens were well tolerated, raltegravir recipients experienced significantly fewer drug-related clinical adverse events than patients on efavirenz (Fig. 1), a more favourable lipid profile and greater increments in CD4 cell counts. These long-term data enhance the role of raltegravir in HIV therapy. Administration is twice daily, however, and there are no single-tablet combinations including raltegravir. Furthermore, raltegravir can rapidly select for drug resistance in patients with viraemia, causing cross-resistance to elvitegravir and partial cross-resistance to dolutegravir (reviewed in [34]). Although raltegravir has an excellent safety track record, there have been cases of rhabdomyolysis reported. Raltegravir causes a
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Antimicrobials
General
Efavirenz Raltegravir
Skin/subcutaneous tissue
Psychiatric
Nervous system
Gastrointestinal
0
20
40
60
% with adverse events
FIGURE 1. STARTMRK trial: proportion of patients experiencing clinical adverse events that were reported as possibly, probably, or definitely drug-related over 240 weeks. Adverse events occurring in at least 5% of patients are shown. Neuropsychiatric side-effects occurred in 39 versus 64% for raltegravir and efavirenz recipients, respectively (P 100 000 copies/ml. Safety events were similarly infrequent in the two arms of SPRING-2. RR in clinical trials did not differ by NRTI backbone, indicating that dolutegravir can compensate for any reduced activity of abacavir at high pre-ART viral load. Dolutegravir has a moderate drug interaction profile [39]. It is primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A1 pathway, and it neither induces nor inhibits CYP isoenzymes. However, dolutegravir reduces tubular secretion of creatinine via inhibition of OCT2, and in the first weeks of therapy causes a moderate and nonprogressive increase in serum creatinine, without affecting the actual GFR. Dolutegravir offers a high genetic barrier to resistance, which may reflect slow dissociation from the integrase enzyme and impaired fitness of resistant mutants [40 ,41 ]. In SINGLE, SPRING-2, and FLAMINGO, none of the dolutegravir recipients who experienced virological failure showed treatment-emergent resistance to any of the components of the regimen. In contrast, treatment-emergent &
Three randomized trials compared the secondgeneration integrase inhibitor dolutegravir with efavirenz (SINGLE) [36 ], raltegravir (SPRING-2) [37 ], or ritonavir-boosted darunavir [38 ], each &&
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Table 5. Clinical trials of dolutegravir for fist-line therapy Response at week 48a
Study
Design
Arms
SINGLE, N ¼ 833
Placebo-controlled
DTG 50 mg OD þ ABC/3TC ODþ (TDC/FTC/EFV placebo OD)
88%
Non-inferiority (10% margin)
TDC/FTC/EFV ODþ (DTG þ ABC/3TC placebo OD)
81%
Placebo-controlled
DTG 50 mg OD þABC/3TC or TDF/FTC ODþ(RAL placebo BID)
88%
Non-inferiority (10% margin)
RAL 400 mg BID þABC/3TC or TDF/FTC ODþ (DTG placebo OD)
85%
Open-label
DTG 50 mg OD þ ABC/3TC or TDF/FTC OD
90%
Non-inferiority (12% margin)
DRV/r 800/100 mg OD þ ABC/3TC or TDF/FTC OD
83%
SPRING-2, N ¼ 822
FLAMING, N ¼ 484
95% CI 2.5, 12.3
2.2, 7.1
0.9, 13.2
Outcome for DTG arm Statistical superiority (P ¼ 0.003)
Non-inferiority
Statistical superiority (P ¼ 0.025)
ABC/3TC, coformulated abacavir/lamivudine; b.i.d., twice daily; CI, confidence interval of adjusted difference; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; OD, once daily; RAL, raltegravir; TDC/FTC/EFV, coformulated tenofovir/emtricitabine/efavirenz. a Proportions with plasma HIV-1 RNA less than 50 copies/ml (US Food and Drug Administration snapshot algorithm).
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HIV: new drugs, new guidelines Geretti and Tsakiroglou
resistance was observed in both the efavirenz arm of SINGLE and the raltegravir arm of SPRING-2. Once-daily dosing (with no food requirement) is an advantage of dolutegravir for first-line ART, and convenience has been further enhanced by the recent approval of a single-tablet once-daily coformulation of dolutegravir/abacavir/lamivudine. Although more clinical experience is needed, these data position dolutegravir at the forefront of available options for the initial treatment of HIV infection, in combination with abacavir (in patients who test HLAB5701 negative) or tenofovir plus lamivudine or emtricitabine, and regardless of the pre-ART viral load [9,10].
Rates of serious or treatment-modifying adverse events were similar between the two arms. Although some of the dual therapy studies now provide a validated treatment option for selected patients, further data on overall benefit over triple ART are required to inform recommended practice.
CONCLUSION New ART options offer an optimal combination of efficacy, safety and convenience, which makes them suitable for early ART initiation. With several compounds – including efavirenz and lamivudine – becoming available as generics, analyses are required of the net benefit of newer agents once the cost of therapy is taken into account [47,48 ]. Willingness and readiness to start therapy, commit to life-long treatment, and observe adherence levels greater than 95% remain important requirements of successful ART and must be discussed with all patients prior to starting therapy. &
THE IMMEDIATE FUTURE Tenofovir has been associated with an increased risk of renal and bone disease, and cohort studies suggest that impact on renal function may be long lasting after tenofovir discontinuation [29 ,31 ]. Tenofovir alafenamide (TAF, GS-7340) is a prodrug that is converted into tenofovir intracellulary. In a phase 2, double-blind randomized trial, the single-tablet coformulation of TAF/FTC/EVG/c caused a smaller impact on proximal tubular function and bone mineral density than TDF/FTC/EVG/c, while maintaining efficacy over 48 weeks [42 ]. Cobicistat is being developed as an alternative to ritonavir for the pharmacoenhancement of protease inhibitors [43], and coformulations of cobicistat with atazanavir or darunavir are becoming available. A single-tablet once-daily combination of TAF/emtricitabine/darunavir/cobicistat is also in clinical development. &
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Acknowledgements None. Conflicts of interest A.M.G. has received consultancy fees, speaker’s fees, and research grants from Gilead, Merck, Janssen, and ViiV/GSK.
REFERENCES AND RECOMMENDED READING
ALTERNATIVES TO TRIPLE THERAPY
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
Several alternatives to triple therapy are being explored with the primary aim of reducing NRTI toxicity. Studies have investigated the combination of one PI/r plus either lamivudine, raltegravir, efavirenz, or the CCR5 antagonist maraviroc, with mixed results. Some dual regimens have yielded promising, proof-of-concept results (for example, ritonavirboosted lopinavir plus either lamivudine [44 ] or raltegravir [45]), whereas others have shown increased toxicity or reduced efficacy (for example, atazanavir plus raltegravir; ritonavir-boosted darunavir plus maraviroc). The open-label NEAT001/ ANRS143 trial randomized 805 ART-naive adults in 15 European countries to receive once-daily ritonavir-boosted darunavir plus either raltegravir twice daily or TDF/FTC once daily [46 ]. Over 96 weeks, the NRTI-sparing arm achieved overall noninferiority; however, reduced potency was observed in patients with CD4 counts less than 200 cells/ml and pre-ART viral load greater than 100 000 copies/ml.
1. Mocroft A, Furrer HJ, Miro JM, et al. The incidence of AIDS-defining illnesses & at a current CD4 count 200 cells/mL in the postcombination antiretroviral therapy era. Clin Infect Dis 2013; 57:1038–1047. Large multicentre European cohort analysis indicating a higher risk of AIDSdefining disease – especially malignancies – in HIV-positive patients with CD4 counts of 500–749 cells/ml relative to individuals with higher counts. The relationship did not change according to whether the viral load was below or above 400 copies. The findings suggest an effect of poor CD4 cell count reconstitution and/or high cumulative exposure to T-cell activation and inflammation, both of which may be modified by early ART initiation. 2. Borges AH, Silverberg MJ, Wentworth D, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS 2013; 27:1433–1441. 3. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute & myocardial infarction. JAMA Intern Med 2013; 173:614–622. Large cohort analysis indicating that HIV infection is associated with a 50% increased risk of acute myocardial infarction, after adjusting for Framingham risk factors, comorbidities, and substance use. An excess risk remained among patients with viral load of less than 500 copies. 4. Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin treatment reduces & markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clin Infect Dis 2014; 58:588–595. This randomized, double-blind, placebo-controlled trial demonstrated that in patients on ART, 24 weeks of rosuvastatin significantly lowered markers of monocyte-activation (for example, sCD14). The findings indicate persistent immune-activation and inflammation in patients receiving ART, highlight the role of monocytes as an important source of inflammation, and point to a potential antiinflammatory benefit of statins in the setting of HIV infection that is independent of the lipid-lowering effect.
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Antimicrobials 5. Le T, Wright EJ, Smith DM, et al. Enhanced CD4þ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med 2013; 368:218–230. This prospective, observational cohort analysis of persons with acute or early HIV-1 infection demonstrated that both the likelihood of CD4 counts increasing to at least 900 cells/ml and the rate of CD4 cell count recovery were significantly lower if ART was initiated after the first 4 months of the estimated date of infection rather than earlier. 6. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus & delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis 2014; 14:281–290. The HPTN 052 trial randomized the HIV-positive partner of serodiscordant couples to either immediate or deferred ART. One important – previously reported – benefit of early ART was that it reduced HIV transmission by 96%. In this analysis, early ART was associated with a reduced incidence of clinical events (especially AIDS disease and tuberculosis). Median CD4 counts at the start of ART were 442 cells/ml in the early treatment group and 230 cells/ml in the deferred treatment group. Thus, the study provides evidence that starting ART when the CD4 count is between 350 and 500 cells/ml is preferable to waiting until it declines significantly below 350 cells/ml. 7. Anglemyer A, Rutherford GW, Horvath T, et al. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. Cochrane Database Syst Rev 2013; 4:CD009153. 8. Tanser F, Barnighausen T, Grapsa E, et al. High coverage of ART associated && with decline in risk of HIV acquisition in rural KwaZulu-Natal. Science 2013; 339:966–971. Seminal study indicating that substantial reductions in HIV transmission can be achieved by widespread adoption of ART within high-prevalence settings in subSaharan Africa. Questions that remain to be addressed include durability of protection, long-term adherence, likelihood of transmission of ART-resistant strains, and overall levels of ART coverage required to substantially affect transmission in different epidemiological settings. 9. Gu¨nthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA 2014; 312:410–425. 10. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. May 2014. http://aidsinfo.nih.gov/ guidelines/html/1/adult-and-adolescent-arv-guidelines/0/. [Accessed 26 August 2014] 11. World Health Organisation. Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations. July 2014. http:// www.who.int/hiv/pub/guidelines/keypopulations/en/. [Accessed 26 August 2014] 12. European AIDS Clinical Society. Guidelines version 7.02, June 2014. http:// eacsociety.org/Portals/0/140601_EACS%20EN7.02.pdf. [Accessed 26 August 2014] 13. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (updated November 2013). HIV Med 2014; 15 (Suppl 1):1–85. 14. Raffi F, Pozniak AL, Wainberg MA. Has the time come to abandon efavirenz for first-line antiretroviral therapy? J Antimicrob Chemother 2014; 69:1742– 1747. 15. Geretti AM, Fox Z, Johnson JA, et al. Sensitive assessment of the virologic outcomes of stopping and restarting nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. PLoS One 2013; 8: e69266. 16. Li JZ, Paredes R, Ribaudo HJ, et al. Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis. JAMA 2011; 305:1327–1335. 17. Gandhi M, Gandhi RT. Single-pill combination regimens for treatment of HIV-1 infection. N Engl J Med 2014; 371:248–259. 18. Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily & dosing antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials. Clin Infect Dis 2014; 58:1297–1307. Elegant meta-analysis of 19 randomized controlled trials comprising a total of 6312 patients, demonstrating that higher pill burden was associated with both lower adherence rates and worse virological suppression. Adherence, but not virological suppression, was slightly better and decreased less over time with once-daily versus twice-daily regimens. 19. Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized & clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS 2014; 28:989–997. This study reports the week 48 findings from a phase 3b, randomized, open-label, multicentre, international, 96-week noninferiority trial of first-line ART. Among patients with pre-ART viral load less than 100 000 copies, RR were 89% on TDF/FTC/RPV versus 82% on TDF/FTC/EFV (difference 7.2%, 95% CI 1.1– 13.4; P ¼ 0.02), demonstrating statistical superiority of TDF/FTC/RPV. TDF/FTC/ RPV showed reduced potency at high viral load, with the greatest effect seen at greater than 500 000 copies. 20. Nelson MR, Elion RA, Cohen CJ, et al. Rilpivirine versus efavirenz in HIV-1infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE studies. HIV Clin Trials 2013; 14:81–91. &&
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21. Tebas P, Sension M, Arribas J, et al. Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-infected adults treated with rilpivirine or efavirenz for 96 weeks in the ECHO and THRIVE trials. Clin Infect Dis 2014; 59:425–434. The study demonstrated that changes in body fat distribution (by dual-energy X-ray absorptiometry) were similar between rilpivirine and efavirenz, and influenced by the NRTI backbone: at week 96, patients receiving zidovudine/lamivudine had lost limb fat, and those receiving TDF/FTC had gained it. 22. Palella FJ Jr, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/ & tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS 2014; 28:335–344. The study demonstrated that in patients receiving stable, suppressive ART, it is safe to replace a PI/r-based regimen with a single-tablet NNRTI-based combination, provided patients are selected to exclude those that may harbour resistance to any component of the new regimen. 23. Porter DP, Kulkarni R, Fralich T, et al. Characterization of HIV-1 drug resistance development through week 48 in antiretroviral naive subjects on rilpivirine/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF in the STaR study (GS-US-264-0110). J Acquir Immune Defic Syndr 2014; 65:318–326. 24. Molina JM, Clumeck N, Orkin C, et al. Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load 100 000 copies/ mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials. HIV Med 2014; 15:57–62. 25. Xu HT, Colby-Germinario SP, Asahchop EL, et al. Effect of mutations at position E138 in HIV-1 reverse transcriptase and their interactions with the M184I mutation on defining patterns of resistance to nonnucleoside reverse transcriptase inhibitors rilpivirine and etravirine. Antimicrob Agents Chemother 2013; 57:3100–3109. 26. Shah BM, Schafer JJ, Priano J, Squires KE. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy 2013; 33:1107–1116. 27. Wohl DA, Cohen C, Gallant JE, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65:e118–e120. 28. Clumeck N, Molina JM, Henry K, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65:e121–e124. 29. Jose S, Hamzah L, Campbell LJ, et al. Incomplete reversibility of estimated & glomerular filtration rate decline following tenofovir disoproxil fumarate exposure. J Infect Dis 2014; 210:363–373. This cohort analysis demonstrated that one-third of patients who discontinued tenofovir after experiencing a decline in eGFR did not fully recover the eGFR within 6 months of discontinuation. Longer tenofovir exposure reduced the likelihood of a complete recovery, suggesting that prolonged tenofovir exposure at a low eGFR should be avoided. 30. Stray KM, Bam RA, Birkus G, et al. Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir. Antimicrob Agents Chemother 2013; 57:4982–4989. 31. Baxi SM, Greenblatt RM, Bacchetti P, et al. Common clinical conditions – & age, low BMI, ritonavir use, mild renal impairment – affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. AIDS 2014; 28:59–66. Using intensive pharmacokinetic sampling over 24 h in a cohort of HIV-positive women, the study demonstrated that ritonavir use, increasing age, decreasing body mass index, and lower GFR prior to tenofovir initiation were associated with elevated tenofovir exposure during therapy. As elevated exposure increases the risk of drug toxicity, these risk factors should be taken into account when prescribing ART. 32. Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of nonnucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGTY-NNRTI): 48 week results of a randomised, open-label, phase 3b, noninferiority trial. Lancet Infect Dis 2014; 14:590–599. 33. Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, & cobicistat, emtricitabine, and tenofovir versus continuation of ritonavirboosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48-week results of a randomised, open-label, phase 3b, noninferiority trial. Lancet Infect Dis 2014; 14:581–589. The study demonstrated that switching to TDF/FTC/EVG/c was statistically superior to continuing PI/r-based ART. Superiority was mainly caused by a higher number of discontinuations in the PI/r arm for nonvirological reasons; virological failure was rare in both groups. At week 48, RR were 94% for the switch arm versus 87% for the PI/r continuation arm (difference 67%, 95% CI 0.4–13.7; P ¼ 0.025). 34. White KL, Raffi F, Miller MD. Resistance analyses of integrase strand transfer inhibitors within phase 3 clinical trials of treatment-naive patients. Viruses 2014; 6:2858–2879. &
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HIV: new drugs, new guidelines Geretti and Tsakiroglou 35. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63:77–85. The significance of this study relates to the finding that raltegravir was statistically superior to efavirenz over extended follow-up, with RR after 5 years of 71% on raltegravir versus 61% on efavirenz (difference 9.5%, 95% CI 1.7–17.3). 36. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir/lamivudine && for the treatment of HIV-1 infection. N Engl J Med 2013; 369:1807–1818. Large study demonstrating that during 48 weeks of therapy, dolutegravir caused significantly fewer discontinuations for adverse effects than efavirenz (2% versus 10%), with lower incidence of neuropsychiatric events and rash, although insomnia was more frequent. 37. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice&& daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, noninferiority trial. Lancet Infect Dis 2013; 13:927–935. This study presents the week 96 analysis of the first double-blind comparison of two integrase inhibitors for first-line ART. The two arms showed largely similar efficacy, tolerability, and safety profiles. 38. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus && darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383:2222–2231. The study demonstrates better safety and tolerability, and greater potency of dolutegravir compared with the PI/r. Dolutegravir recipients experienced fewer discontinuations due to adverse events or stopping criteria (2% versus 4%), with less diarrhoea (17% versus 29%), more headaches (15% versus 10%), and fewer low-density lipoprotein values of grade 2 or higher (2% versus 7%). 39. Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet 2013; 52:981–994. 40. Mesple`de T, Quashie PK, Osman N, et al. Viral fitness cost prevents HIV-1 & from evading dolutegravir drug pressure. Retrovirology 2013; 10:22. Elegant in-vitro studies that provide a rational for the high genetic barrier to resistance of dolutegravir observed in clinical studies, due to the selection of a dead-end mutational pathway that impairs virus fitness. 41. Oliveira M, Mesple`de T, Quashie PK, et al. Resistance mutations against && dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. AIDS 2014; 28:813–819. Elegant work showing that dolutegravir-resistant mutants (R263K or G118R and/or H51Y) are impaired in their ability to evolve genetically during in-vitro selective passage with lamivudine or nevirapine. This suggests that dolutegravir reduces the emergence of reverse transcriptase mutations, providing a mechanism for the lack of NRTI resistance observed in clinical trials. Further clinical studies are needed to confirm these observations. &
42. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2014; 67:52– 58. The study presents promising data on the short-term safety and efficacy of TAF. 43. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis 2013; 208:32–39. 44. Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir & and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, noninferiority GARDEL trial. Lancet Infect Dis 2014; 14:572–580. Proof-of-concept study, demonstrating that in ART-naı¨ve patients, dual therapy was noninferior to triple therapy, with better safety and tolerability, and preserved potency at high pre-ART viral load. Applicability is limited by the extensive use of zidovudine in the comparator arm, and toxicity concerns over lopinavir/ritonavir use. 45. Haskelberg H, Mallon PW, Hoy J, et al. Bone mineral density over 96 weeks in adults failing first-line therapy randomised to raltegravir/lopinavir/ritonavir compared to standard second-line therapy. J Acquir Immune Defic Syndr 2014; 67:161–168. 46. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined && with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised noninferiority trial. Lancet 2014. [Epub ahead of print] Proof-of-concept study demonstrating that in ART-naı¨ve patients, dual therapy was noninferior to triple therapy. There was no substantial difference in safety and tolerability between the two arms; however, dual therapy was virologically less potent in patients with low CD4 counts and high pre-ART viral load. These data suggest that the combination of darunavir/ritonavir once daily plus raltegravir is not as virologically potent as the combination of lopinavir/ritonavir twice daily plus lamivudine. 47. Walensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med 2013; 158:84–92. 48. Engsig FN, Gerstoft J, Helleberg M, et al. Effectiveness of antiretroviral & therapy in individuals who for economic reasons were switched from a once-daily single-tablet regimen to a triple-tablet regimen. J Acquir Immune Defic Syndr 2014; 66:407–413. Interesting study showing that in an advanced healthcare setting in Europe, switching from a branded, single-tablet combination to a generic triple-tablet combination can realize important economic savings with negligible short-term risk of adverse outcomes. &
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HIV: new drugs, new guidelines Anna Maria Geretti and Maria Tsakiroglou
Purpose of review This review discusses recent changes in HIV treatment guidelines, focussing on the optimal time for starting antiretroviral therapy (ART) in chronic asymptomatic infection, and treatment options for ART-naı¨ve patients. Recent findings Understanding of HIV pathogenesis has progressed significantly, with a growing appreciation of the role of HIV replication in causing inflammation and promoting both AIDS and non-AIDS diseases. Early suppression of HIV replication with ART benefits the individual, and by reducing transmission and promoting engagement with care also brings public health benefits. For years, efavirenz-based ART was favoured by treatment guidelines, reflecting unsurpassed performance in clinical trials. New treatment options show high efficacy and safety and include single-tablet coformulations for once-daily dosing to improve convenience. Recent data have demonstrated superiority over efavirenz of regimens based on rilpivirine in patients with low pre-ART HIV-1 RNA load and raltegravir or dolutegravir regardless of the viral load. Summary Some guidelines now recommend starting ART regardless of CD4 cell counts, whereas others take a more cautious approach pending results from studies that are testing the clinical benefit of early therapy. New treatment options allow therapy to be tailored to the patient’s circumstances and are suitable for early ART initiation. Keywords antiretroviral therapy, CD4 count, clinical trials, guidelines
INTRODUCTION
that the effect may persist after starting ART [2,3 ,4 ]. At the same time, efforts to develop an HIV cure have highlighted the importance of preserving – rather than restoring – immune function, which is more likely if ART is initiated earlier rather than later [5 ]. These factors provide a strong rational for the concept that suppression of HIV replication offsets any potential negative effects of treatment even at high CD4 cell counts. Data indicating a clinical benefit of early ART come from observational cohorts and secondary analyses of clinical trials, and there remains a paucity of controlled studies designed to address the question. Evidence favours starting ART when the CD4 count is between 350 and 500 cells/ml compared with &
The incidence of AIDS-defining disease is low when CD4 counts are greater than 350 cells/ml and for many years, the potential benefits of starting antiretroviral therapy (ART) earlier had to be balanced against the potential risks of life-long treatment, primarily drug toxicity, and lapses in adherence leading to drug resistance and exhaustion of treatment options. Major advances in our understanding of HIV pathogenesis, and the introduction of well tolerated, effective, and convenient treatment options, are gradually shifting opinions (Table 1).
STARTING ANTIRETROVIRAL THERAPY IN CHRONIC ASYMPTOMATIC HIV INFECTION Observational cohorts show a small, but persistent, risk of AIDS-defining disease – especially malignancies – at CD4 counts of 500–749 cells/ml relative to patients with higher counts [1 ]. There has been growing appreciation that HIV replication, by inducing chronic T-cells activation and inflammation, also increases the incidence of non-AIDS illnesses (for example, cardiovascular disease), and &
&
&&
Department of Clinical Infection, Microbiology & Immunology, Institute of Infection & Global Health, University of Liverpool, Liverpool, UK Correspondence to Professor Anna Maria Geretti, MD, PhD, Department of Clinical Infection, Microbiology & Immunology, Institute of Infection & Global Health, University of Liverpool, 8 West Derby Street, Liverpool L69 7BE, UK. Tel: +44 151 795 9665; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:545–553 DOI:10.1097/QCO.0000000000000106
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Antimicrobials
KEY POINTS The goals of ART are to reduce HIV-related disease, impact of comorbidities, and risk of HIV transmission. Advances in our understanding of HIV pathogenesis provide a strong rational for early treatment initiation. HIV treatment has made dramatic advances in the last two decades. Some new drugs show higher efficacy – predominantly through improved safety and tolerability – than the efavirenz-based standard of care. Most regimens for first-line therapy have features that make them less suitable for certain patient groups. The recently approved integrase inhibitor dolutegravir – now also available in single-tablet coformulation with abacavir and lamivudine – offers excellent efficacy, safety and tolerability, a high genetic barrier to resistance, once-daily dosing without food requirements, and moderate potential for drug–drug interactions. Clinical experience remains limited. Cost–benefit analyses will test new treatments against older options that are now becoming available as generics, including efavirenz and lamivudine.
starting when the CD4 count is well below 350 cells/ml [6 ]; the benefit of starting ART at a CD4 count greater than 500 cells/ml is unclear. The Strategic Timing of Antiretroviral Treatment study is a randomized trial that will use a composite primary end-point of AIDS diagnoses, serious non-AIDS diagnoses, and all-cause mortality to compare immediate versus delayed ART in patients with CD4 counts
greater than 500 cells/ml. The trial is expected to report in 2016. There is unequivocal evidence that in HIVdiscordant couples, treatment of the positive partner significantly lowers the probability of transmission to the uninfected partner [7]. Increasing ART coverage also affects a substantial decline in HIV incidence at the population level. In challenging, high-prevalence settings in sub-Saharan Africa, HIV-uninfected individuals living in a community with ART coverage of 30–40% are 38% less likely to acquire HIV than someone living in a community in which ART coverage is less than 10% [8 ]. These considerations have brought important changes in treatment guidelines, and some panels have expressed the consensus that a ‘test and treat’ approach should be favoured, whereby ART is started regardless of the CD4 cell count (Table 2) [9,10]. Some experts advocate a more cautious approach and emphasize that the decision to start treatment when the CD4 count is greater than 350 cells/ml must consider available resources, local programmatic needs, and the patient’s circumstances (Table 3), taking into account age, comorbidities, transmission risk, and the individual’s preference [11–13]. &&
&
EFAVIRENZ FOR THE INITIAL TREATMENT OF HIV INFECTION The combination of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz with two nucleoside or nucleotide reverse transcriptase
Table 1. Considerations in favour of early initiation of antiretroviral therapy Factor
Mechanism
Outcome
Virus
Ongoing replication
Immunodeficiency and opportunistic disease Chronic T-cell activation and inflammation causes immunosenescence and accelerated ageing of systems and functions (e.g., cardiovascular, kidney, liver, and neurocognitive) Increased risk of malignancies Accelerated progression of chronic viral hepatitis Increased risk of transmission High viral reservoirs and impaired immune function reduce the likelihood of success of potential curative strategies
Treatment
New drugs
Improved efficacy reduces the risk of failure and drug resistance Improved tolerability facilitates adherence Improved safety reduces long-term toxicity
Coformulations Patient
546
Reduced pill burden and dosing frequency improve convenience
Ageing
Older patients are at increased risk of both AIDS and non-AIDS morbidities
Long-term survival
Unmasking of comorbidities (e.g., cardiovascular, renal, and bone disease); impact of coinfections (e.g., chronic viral hepatitis)
Engagement
Treatment promotes retention into care
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HIV: new drugs, new guidelines Geretti and Tsakiroglou Table 2. CD4 cell count cut-offs for starting antiretroviral therapy in chronic asymptomatic HIV infectiona CD4 count Guideline
350–500 (cells/ml)
>500 (cells/ml)
IAS, USA, July 2014b
Offer (A1a)
Offer (BIII)
DHHS, USA, May 2014c
Offer (AII)
Offer (BIII)
WHO, July 2014
Offer
Offer if HBV with severe liver disease; active TB; HIV serodiscordant couple; or for programmatic and operational reasons, particularly in generalized epidemics
EACS, Europe, June 2014
Consider
Consider
Offer if HBV or HCV
Offer if HBV requiring treatment
Offer at any CD4 count if non-AIDS HIV-related disease (kidney disease, NC impairment, HL, HPV-associated cancers) Consider at any CD4 count in order to reduce transmission BHIVA, UK, November 2013d
Offer if HBV (1B) or HCV (1C)
Offer if HBV requiring treatment (2B)
Offer at any CD4 count if non-AIDS HIV-related disease (kidney disease, ITP, NC impairment); malignancy requiring immunosuppressive radiotherapy/chemotherapy (1C); or patient wishes to reduce risk of transmission to partners (GPP) BHIVA, British HIV Association; DHSS, Department of Health & Social Security; EACS, European AIDS Clinical Society; HBV, hepatitis B virus; HCV, hepatitis C virus; HL, Hodgkin’s lymphoma; HPV, human papilloma virus; IAS, International Antiviral Society; ITP, idiopathic thrombocytopenic purpura; NC, neurocognitive; TB, tuberculosis. a All guidelines recommend treatment at a CD4 count less than 350 cells/ml. b Strength of recommendation: A ¼ strong; B ¼ moderate. Quality of evidence: Ia ¼ at least one randomized clinical trial published in peer-reviewed literature; III ¼ panel’s analysis of available evidence. c Strength of recommendation: A ¼ strong; B ¼ moderate. Quality of evidence: II ¼ data from well designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III ¼ expert opinion. d Strength of recommendation: 1 ¼ strong; 2 ¼ moderate/optional. Quality of evidence: B ¼ moderate (randomized trials that suffer from limitations, or observational studies with consistent effects and exclusion of most potential sources of bias); C ¼ low (controlled trials with several very serious limitations or observational studies with limited evidence on effects and exclusion of most potential sources of bias); GPP ¼ good practice points, on the basis of expert opinion.
Table 3. Factors that guide initial treatment selection in HIV care Virus
Transmitted drug-resistance Pretreatment HIV-1 RNA load
Treatment
Safety profile Convenience of dosing Food requirements Known or potential drug interactions Genetic barrier to resistance Cost
Patient
Adherence potential Comorbidties Employment and life style Personal preferences Drug abuse or dependency HLA-B5701 status (for abacavir) Pretreatment CD4 cell count Pregnancy
inhibitors (NRTIs) – typically tenofovir and emtricitabine – has long served as the reference standard of care in clinical trials of first-line ART and has been a recommended option in treatment guidelines (Table 4). The preference is based on a long-standing record of efficacy and safety, convenience of oncedaily dosing, availability of a single-tablet coformulation with tenofovir and emtricitabine (Atripla), and a long half-life that forgives the occasional missed dose. In head-to-head comparisons with efavirenz, several antiretrovirals have shown a reduced incidence of side-effects that are typically associated with efavirenz use – primarily central nervous system (CNS) disturbances, skin rashes, and dyslipidaemia. Until recently, however, efavirenz-based ART remained unsurpassed in randomized trials using rates of HIV-1 RNA suppression and incidence and severity of adverse events as surrogate marker endpoints for clinical efficacy. The preferred use of efavirenz has been called into question (reviewed in [14]). To minimize the
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Antimicrobials Table 4. Preferred regimens for the initial treatment of HIV infection in Europe and North Americaa Guideline
NRTI backbone
Third agent
IAS, USA, July 2014
TDF/FTC
NNRTI: EFV, RPVb INI: DTG, EVG/cc, RAL PI: ATVþr, DRVþr
ABCd/3TC
NNRTI: EFVb INI: DTG PI: ATVþrb
DHHS, USA, May 2014
TDF/FTC or TDF þ 3TC
NNRTI: EFV, RPVb,e INI: DTG, EVG/cc, RAL PI: ATVþr, DRVþr
ABCd/3TC or ABCd þ FTC
TDF/FTC or ABCd/3TC
TDF/FTC
NNRTI: EFV, RPVb c
INI: EVG/c , RAL NNRTI: EFV INI: EVG/cc, RAL PI: ATVþr, DRVþr
3TC, lamivudine; ABC, abacavir; ATVþr, ritonavir-boosted atazanavir; DRVþr, ritonavir-boosted darunavir; DTG, dolutegravir; EFV, rfavirenz; EVG/ c, elvitegravir/cocibistat; FTC, emtricitabine; INI, integrase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside or nucleotide reverse transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir. a Regimens are listed by drug class and in alphabetical order. b Only if baseline plasma HIV-1 RNA load less than 100 000 copies/ml. c Only if pre-ART creatinine clearance greater than 70 ml/min. d Only if HLA-B5701 negative: some guidelines recommend caution with abacavir in patients with high risk for cardiovascular disease because of a proposed link between the drug and myocardial infarction; the link remains controversial. e Only if baseline CD4 count greater than 200 cells/ml.
impact of CNS side-effects, dosing must take place at night on an empty stomach (food increases absorption), which is not always convenient. There is a possible increase in neural tube defects in new-borns of mothers exposed to efavirenz during early pregnancy, renewing concerns about use in women of childbearing potential. Furthermore, although some of the typical neuropsychiatric side-effects (for example, dizziness and abnormal dreams) are often self-limited and not a frequent cause of discontinuation, there is growing awareness of long-term CNS disturbances, including a possible increased tendency to commit suicide in efavirenz recipients. Although the long half-life of efavirenz offers forgiveness, the shorter half-life of accompanying NRTIs can result in a period of inadvertent monotherapy if all treatment is stopped simultaneously, resulting in the selection of NNRTI resistance [15]. A single mutation in reverse transcriptase – typically K103N – is 548
New treatment options show improved safety and tolerability relative to efavirenz, while preserving virological and immunological efficacy. Several are available as single tablets for once-daily dosing, thus improving convenience and facilitating longterm adherence (reviewed in [17,18 ]). &
TENOFOVIR/EMTRICITABINE/RILPIVIRINE (COMPLERA OR EVIPLERA)
INI: DTG
PI: ATVþr, DRVþr BHIVA, UK, Nov 2013
NEW OPTIONS FOR THE INITIAL TREATMENT OF HIV INFECTION
NNRTI: EFVb PI: ATVþrb
EACS, Europe, June 2014
sufficient to abrogate the activity of efavirenz, which makes efavirenz vulnerable to both treatmentemergent and transmitted drug resistance [16].
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The STaR study was the first randomized trial in which all patients (n ¼ 786) took a single-tablet once-daily regimen without additional placebo, comprising either tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV) or tenofovir/emtricitabine/ efavirenz (TDF/FTC/EFV). Among patients with pre-ART viral load of less than 100 000 copies/ml, the response rates (RR) at week 48 were significantly higher in rilpivirine recipients, reflecting greater safety and tolerability and fewer discontinuations for adverse events [19 ]. In patients with a pre-ART viral load of greater than 100 000 copies/ml, higher rates of discontinuation due to adverse events in the TDF/FTC/EFV arm were balanced by higher rates of virological failure in the TDF/FTC/RPV arm, with resulting noninferiority. Similar findings were reported from the ECHO and THRIVE trials of coformulated tenofovir/emtricitabine (TDF/FTC) plus rilpivirine or efavirenz [20]. Thus, within the NNRTI class, rilpivirine offers a valid alternative to efavirenz for patients with favourable pre-ART parameters. Reduced CNS toxicity allows dosing at any time; however, for optimal absorption, rilpivirine must be taken with a solid meal and cannot be taken with proton-pump inhibitors. There is otherwise a low potential for drug–drug interactions. Rilpivirine is a weak inhibitor of the renal tubular transporter OCT2 (organic cation transporter 2) and in the first weeks of therapy causes a small and nonprogressive increase in serum creatinine concentration, which translates into reduced creatinine clearance and estimated glomerular filtration rate (eGFR). No renal safety concerns have emerged from clinical trials. Rilpivirine has less potential for causing dyslipidaemia than both efavirenz [19 ,21 ] and protease inhibitors [22 ]. In a randomized study, switching from a ritonavir-boosted protease inhibitor (PI/r, predominantly atazanavir, lopinavir, or darunavir) &
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HIV: new drugs, new guidelines Geretti and Tsakiroglou
plus two NRTIs (predominantly TDF/FTC) to TDF/ FTC/RPV maintained virological suppression over 48 weeks and significantly improved total cholesterol, low-density lipoprotein, and triglycerides [22 ]. Eligibility criteria were viral load suppression for at least 6 months, lack of previous NNRTI experience, and anticipated full activity of the NRTI backbone. Rilpivirine has a low genetic barrier to resistance, which makes TDF/FTC/RPV unsuitable for patients who may harbour resistance to any of its components. Among patients experiencing virological failure in clinical trials, treatment-emergent resistance to at least one regimen component occurred more frequently with rilpivirine than with efavirenz, particularly at high pre-ART viral load [23]. At low viral load, rilpivirine recipients had a similar incidence of NNRTI resistance (predominantly involving reverse transcriptase positions E138 and Y181) as those on efavirenz, but higher incidence of NRTI resistance (predominantly M184I/V) [24]. Interactions between the E138 and M184 mutational pathways explain these observations [25]. &
TENOFOVIR/EMTRICITABINE/ ELVITEGRAVIR/COBICISTAT (STRIBILD) The integrase inhibitor elvitegravir is primarily metabolized in the liver and intestines via the cytochrome P450 isoenzyme 3A4 pathway and must be taken with the cytochrome P450 isoenzyme 3A4 inhibitor cobicistat (and food) to obtain effective concentrations [26]. There is a resulting high potential for drug–drug interactions (for example, with both rifampicin and rifabutin, precluding use during concomitant tuberculosis therapy). In clinical trials of first-line ART, tenofovir/emtricitabine/elvitegravir/cobicistat (TDF/FTC/EVG/c) was noninferior to both TDF/FTC/EFV (study 102; n ¼ 700) and TDF/FTC plus ritonavir-boosted atazanavir (study 103; n ¼ 708) at week 48, and high RR were maintained across all arms through 144 weeks [27,28]. Self-limiting nausea was the most commonly reported side-effect. In study 102, more TDF/FTC/EVG/c recipients experienced increases in serum creatinine than patients on TDF/FTC/ EFV. The increase occurred within the first 4 weeks of treatment and usually plateaued subsequently without further increases through week 144. Like ritonavir, cobicistat inhibits the renal tubular transporter MATE-1 (multidrug and toxin extrusion transporter 1), reducing creatinine secretion without affecting the actual GFR. However, several cases of renal tubular disease occurred in low-risk individuals exposed to TDF/FTC/EVG/c in clinical trials. Although cobicistat is not thought to affect the
elimination of tenofovir, an interaction cannot be excluded which may enhance the tubular toxicity of tenofovir [29 ,30,31 ]. Monitoring of renal function is recommended. TDF/FTC/EVG/c offers another valuable option for patients who need to switch ART to improve tolerability or convenience. The open-label STRA TEGY trials randomized patients receiving TDF/FTC plus either an NNRTI (78% efavirenz) or a PI/r (40% atazanavir and 40% darunavir) to continue the current ART regimen or to switch to TDF/FTC/EVG/c [32,33 ]. Eligibility criteria were a suppressed viral load for at least 6 months, no prior virological failure, expected full activity of the NRTI backbone, and eGFR at least 70 ml/min. After 48 weeks, TDF/FTC/ EVG/c (n ¼ 290) showed noninferiority relative to continuing the NNRTI (n ¼ 143), albeit with better CNS tolerability. Relative to the PI/r continuation arm (n ¼ 140), TDF/FTC/EVG/c (n ¼ 293) showed significantly higher RR, accompanied by a significant decline in triglycerides, and more nausea, but reduced diarrhoea and bloating. TDF/FTC/EVG/c is not an option for ART-experienced patients who may harbour resistance to any of its component. Elvitegravir has a low genetic barrier to resistance and both NRTI resistance and integrase inhibitor resistance occur at virological failure, with cross-resistance to raltegravir and, partially, to dolutegravir (reviewed in [34]). &
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RALTEGRAVIR Raltegravir is a well established treatment option for ART-naı¨ve patients, reflecting high efficacy and tolerability, and the added advantage of a low potential for drug–drug interactions. The double-blind STARTMRK trial randomized 566 ART-naı¨ve patients to TDF/FTC plus either raltegravir or efavirenz. The trial was originally planned for 96 weeks and then extended. At the 5-year study conclusion, RR were significantly higher in the raltegravir arm [35 ]. Although both regimens were well tolerated, raltegravir recipients experienced significantly fewer drug-related clinical adverse events than patients on efavirenz (Fig. 1), a more favourable lipid profile and greater increments in CD4 cell counts. These long-term data enhance the role of raltegravir in HIV therapy. Administration is twice daily, however, and there are no single-tablet combinations including raltegravir. Furthermore, raltegravir can rapidly select for drug resistance in patients with viraemia, causing cross-resistance to elvitegravir and partial cross-resistance to dolutegravir (reviewed in [34]). Although raltegravir has an excellent safety track record, there have been cases of rhabdomyolysis reported. Raltegravir causes a
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Antimicrobials
General
Efavirenz Raltegravir
Skin/subcutaneous tissue
Psychiatric
Nervous system
Gastrointestinal
0
20
40
60
% with adverse events
FIGURE 1. STARTMRK trial: proportion of patients experiencing clinical adverse events that were reported as possibly, probably, or definitely drug-related over 240 weeks. Adverse events occurring in at least 5% of patients are shown. Neuropsychiatric side-effects occurred in 39 versus 64% for raltegravir and efavirenz recipients, respectively (P 100 000 copies/ml. Safety events were similarly infrequent in the two arms of SPRING-2. RR in clinical trials did not differ by NRTI backbone, indicating that dolutegravir can compensate for any reduced activity of abacavir at high pre-ART viral load. Dolutegravir has a moderate drug interaction profile [39]. It is primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A1 pathway, and it neither induces nor inhibits CYP isoenzymes. However, dolutegravir reduces tubular secretion of creatinine via inhibition of OCT2, and in the first weeks of therapy causes a moderate and nonprogressive increase in serum creatinine, without affecting the actual GFR. Dolutegravir offers a high genetic barrier to resistance, which may reflect slow dissociation from the integrase enzyme and impaired fitness of resistant mutants [40 ,41 ]. In SINGLE, SPRING-2, and FLAMINGO, none of the dolutegravir recipients who experienced virological failure showed treatment-emergent resistance to any of the components of the regimen. In contrast, treatment-emergent &
Three randomized trials compared the secondgeneration integrase inhibitor dolutegravir with efavirenz (SINGLE) [36 ], raltegravir (SPRING-2) [37 ], or ritonavir-boosted darunavir [38 ], each &&
&&
&&
&&
Table 5. Clinical trials of dolutegravir for fist-line therapy Response at week 48a
Study
Design
Arms
SINGLE, N ¼ 833
Placebo-controlled
DTG 50 mg OD þ ABC/3TC ODþ (TDC/FTC/EFV placebo OD)
88%
Non-inferiority (10% margin)
TDC/FTC/EFV ODþ (DTG þ ABC/3TC placebo OD)
81%
Placebo-controlled
DTG 50 mg OD þABC/3TC or TDF/FTC ODþ(RAL placebo BID)
88%
Non-inferiority (10% margin)
RAL 400 mg BID þABC/3TC or TDF/FTC ODþ (DTG placebo OD)
85%
Open-label
DTG 50 mg OD þ ABC/3TC or TDF/FTC OD
90%
Non-inferiority (12% margin)
DRV/r 800/100 mg OD þ ABC/3TC or TDF/FTC OD
83%
SPRING-2, N ¼ 822
FLAMING, N ¼ 484
95% CI 2.5, 12.3
2.2, 7.1
0.9, 13.2
Outcome for DTG arm Statistical superiority (P ¼ 0.003)
Non-inferiority
Statistical superiority (P ¼ 0.025)
ABC/3TC, coformulated abacavir/lamivudine; b.i.d., twice daily; CI, confidence interval of adjusted difference; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; OD, once daily; RAL, raltegravir; TDC/FTC/EFV, coformulated tenofovir/emtricitabine/efavirenz. a Proportions with plasma HIV-1 RNA less than 50 copies/ml (US Food and Drug Administration snapshot algorithm).
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HIV: new drugs, new guidelines Geretti and Tsakiroglou
resistance was observed in both the efavirenz arm of SINGLE and the raltegravir arm of SPRING-2. Once-daily dosing (with no food requirement) is an advantage of dolutegravir for first-line ART, and convenience has been further enhanced by the recent approval of a single-tablet once-daily coformulation of dolutegravir/abacavir/lamivudine. Although more clinical experience is needed, these data position dolutegravir at the forefront of available options for the initial treatment of HIV infection, in combination with abacavir (in patients who test HLAB5701 negative) or tenofovir plus lamivudine or emtricitabine, and regardless of the pre-ART viral load [9,10].
Rates of serious or treatment-modifying adverse events were similar between the two arms. Although some of the dual therapy studies now provide a validated treatment option for selected patients, further data on overall benefit over triple ART are required to inform recommended practice.
CONCLUSION New ART options offer an optimal combination of efficacy, safety and convenience, which makes them suitable for early ART initiation. With several compounds – including efavirenz and lamivudine – becoming available as generics, analyses are required of the net benefit of newer agents once the cost of therapy is taken into account [47,48 ]. Willingness and readiness to start therapy, commit to life-long treatment, and observe adherence levels greater than 95% remain important requirements of successful ART and must be discussed with all patients prior to starting therapy. &
THE IMMEDIATE FUTURE Tenofovir has been associated with an increased risk of renal and bone disease, and cohort studies suggest that impact on renal function may be long lasting after tenofovir discontinuation [29 ,31 ]. Tenofovir alafenamide (TAF, GS-7340) is a prodrug that is converted into tenofovir intracellulary. In a phase 2, double-blind randomized trial, the single-tablet coformulation of TAF/FTC/EVG/c caused a smaller impact on proximal tubular function and bone mineral density than TDF/FTC/EVG/c, while maintaining efficacy over 48 weeks [42 ]. Cobicistat is being developed as an alternative to ritonavir for the pharmacoenhancement of protease inhibitors [43], and coformulations of cobicistat with atazanavir or darunavir are becoming available. A single-tablet once-daily combination of TAF/emtricitabine/darunavir/cobicistat is also in clinical development. &
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Acknowledgements None. Conflicts of interest A.M.G. has received consultancy fees, speaker’s fees, and research grants from Gilead, Merck, Janssen, and ViiV/GSK.
REFERENCES AND RECOMMENDED READING
ALTERNATIVES TO TRIPLE THERAPY
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
Several alternatives to triple therapy are being explored with the primary aim of reducing NRTI toxicity. Studies have investigated the combination of one PI/r plus either lamivudine, raltegravir, efavirenz, or the CCR5 antagonist maraviroc, with mixed results. Some dual regimens have yielded promising, proof-of-concept results (for example, ritonavirboosted lopinavir plus either lamivudine [44 ] or raltegravir [45]), whereas others have shown increased toxicity or reduced efficacy (for example, atazanavir plus raltegravir; ritonavir-boosted darunavir plus maraviroc). The open-label NEAT001/ ANRS143 trial randomized 805 ART-naive adults in 15 European countries to receive once-daily ritonavir-boosted darunavir plus either raltegravir twice daily or TDF/FTC once daily [46 ]. Over 96 weeks, the NRTI-sparing arm achieved overall noninferiority; however, reduced potency was observed in patients with CD4 counts less than 200 cells/ml and pre-ART viral load greater than 100 000 copies/ml.
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Single-pill combination regimens for treatment of HIV-1 infection. N Engl J Med 2014; 371:248–259. 18. Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily & dosing antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials. Clin Infect Dis 2014; 58:1297–1307. Elegant meta-analysis of 19 randomized controlled trials comprising a total of 6312 patients, demonstrating that higher pill burden was associated with both lower adherence rates and worse virological suppression. Adherence, but not virological suppression, was slightly better and decreased less over time with once-daily versus twice-daily regimens. 19. Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized & clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS 2014; 28:989–997. 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21. Tebas P, Sension M, Arribas J, et al. Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-infected adults treated with rilpivirine or efavirenz for 96 weeks in the ECHO and THRIVE trials. Clin Infect Dis 2014; 59:425–434. The study demonstrated that changes in body fat distribution (by dual-energy X-ray absorptiometry) were similar between rilpivirine and efavirenz, and influenced by the NRTI backbone: at week 96, patients receiving zidovudine/lamivudine had lost limb fat, and those receiving TDF/FTC had gained it. 22. Palella FJ Jr, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/ & tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS 2014; 28:335–344. The study demonstrated that in patients receiving stable, suppressive ART, it is safe to replace a PI/r-based regimen with a single-tablet NNRTI-based combination, provided patients are selected to exclude those that may harbour resistance to any component of the new regimen. 23. Porter DP, Kulkarni R, Fralich T, et al. Characterization of HIV-1 drug resistance development through week 48 in antiretroviral naive subjects on rilpivirine/emtricitabine/tenofovir DF or efavirenz/emtricitabine/tenofovir DF in the STaR study (GS-US-264-0110). J Acquir Immune Defic Syndr 2014; 65:318–326. 24. Molina JM, Clumeck N, Orkin C, et al. Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load 100 000 copies/ mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials. HIV Med 2014; 15:57–62. 25. Xu HT, Colby-Germinario SP, Asahchop EL, et al. Effect of mutations at position E138 in HIV-1 reverse transcriptase and their interactions with the M184I mutation on defining patterns of resistance to nonnucleoside reverse transcriptase inhibitors rilpivirine and etravirine. Antimicrob Agents Chemother 2013; 57:3100–3109. 26. Shah BM, Schafer JJ, Priano J, Squires KE. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy 2013; 33:1107–1116. 27. Wohl DA, Cohen C, Gallant JE, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65:e118–e120. 28. Clumeck N, Molina JM, Henry K, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65:e121–e124. 29. Jose S, Hamzah L, Campbell LJ, et al. Incomplete reversibility of estimated & glomerular filtration rate decline following tenofovir disoproxil fumarate exposure. J Infect Dis 2014; 210:363–373. This cohort analysis demonstrated that one-third of patients who discontinued tenofovir after experiencing a decline in eGFR did not fully recover the eGFR within 6 months of discontinuation. Longer tenofovir exposure reduced the likelihood of a complete recovery, suggesting that prolonged tenofovir exposure at a low eGFR should be avoided. 30. Stray KM, Bam RA, Birkus G, et al. Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir. Antimicrob Agents Chemother 2013; 57:4982–4989. 31. Baxi SM, Greenblatt RM, Bacchetti P, et al. Common clinical conditions – & age, low BMI, ritonavir use, mild renal impairment – affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. AIDS 2014; 28:59–66. Using intensive pharmacokinetic sampling over 24 h in a cohort of HIV-positive women, the study demonstrated that ritonavir use, increasing age, decreasing body mass index, and lower GFR prior to tenofovir initiation were associated with elevated tenofovir exposure during therapy. As elevated exposure increases the risk of drug toxicity, these risk factors should be taken into account when prescribing ART. 32. Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of nonnucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGTY-NNRTI): 48 week results of a randomised, open-label, phase 3b, noninferiority trial. Lancet Infect Dis 2014; 14:590–599. 33. Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, & cobicistat, emtricitabine, and tenofovir versus continuation of ritonavirboosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48-week results of a randomised, open-label, phase 3b, noninferiority trial. Lancet Infect Dis 2014; 14:581–589. The study demonstrated that switching to TDF/FTC/EVG/c was statistically superior to continuing PI/r-based ART. Superiority was mainly caused by a higher number of discontinuations in the PI/r arm for nonvirological reasons; virological failure was rare in both groups. At week 48, RR were 94% for the switch arm versus 87% for the PI/r continuation arm (difference 67%, 95% CI 0.4–13.7; P ¼ 0.025). 34. White KL, Raffi F, Miller MD. Resistance analyses of integrase strand transfer inhibitors within phase 3 clinical trials of treatment-naive patients. Viruses 2014; 6:2858–2879. &
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HIV: new drugs, new guidelines Geretti and Tsakiroglou 35. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63:77–85. The significance of this study relates to the finding that raltegravir was statistically superior to efavirenz over extended follow-up, with RR after 5 years of 71% on raltegravir versus 61% on efavirenz (difference 9.5%, 95% CI 1.7–17.3). 36. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir/lamivudine && for the treatment of HIV-1 infection. N Engl J Med 2013; 369:1807–1818. Large study demonstrating that during 48 weeks of therapy, dolutegravir caused significantly fewer discontinuations for adverse effects than efavirenz (2% versus 10%), with lower incidence of neuropsychiatric events and rash, although insomnia was more frequent. 37. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice&& daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, noninferiority trial. Lancet Infect Dis 2013; 13:927–935. This study presents the week 96 analysis of the first double-blind comparison of two integrase inhibitors for first-line ART. The two arms showed largely similar efficacy, tolerability, and safety profiles. 38. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus && darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383:2222–2231. The study demonstrates better safety and tolerability, and greater potency of dolutegravir compared with the PI/r. Dolutegravir recipients experienced fewer discontinuations due to adverse events or stopping criteria (2% versus 4%), with less diarrhoea (17% versus 29%), more headaches (15% versus 10%), and fewer low-density lipoprotein values of grade 2 or higher (2% versus 7%). 39. Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet 2013; 52:981–994. 40. Mesple`de T, Quashie PK, Osman N, et al. Viral fitness cost prevents HIV-1 & from evading dolutegravir drug pressure. Retrovirology 2013; 10:22. Elegant in-vitro studies that provide a rational for the high genetic barrier to resistance of dolutegravir observed in clinical studies, due to the selection of a dead-end mutational pathway that impairs virus fitness. 41. Oliveira M, Mesple`de T, Quashie PK, et al. Resistance mutations against && dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. AIDS 2014; 28:813–819. Elegant work showing that dolutegravir-resistant mutants (R263K or G118R and/or H51Y) are impaired in their ability to evolve genetically during in-vitro selective passage with lamivudine or nevirapine. This suggests that dolutegravir reduces the emergence of reverse transcriptase mutations, providing a mechanism for the lack of NRTI resistance observed in clinical trials. Further clinical studies are needed to confirm these observations. &
42. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2014; 67:52– 58. The study presents promising data on the short-term safety and efficacy of TAF. 43. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis 2013; 208:32–39. 44. Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir & and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, noninferiority GARDEL trial. Lancet Infect Dis 2014; 14:572–580. Proof-of-concept study, demonstrating that in ART-naı¨ve patients, dual therapy was noninferior to triple therapy, with better safety and tolerability, and preserved potency at high pre-ART viral load. Applicability is limited by the extensive use of zidovudine in the comparator arm, and toxicity concerns over lopinavir/ritonavir use. 45. Haskelberg H, Mallon PW, Hoy J, et al. Bone mineral density over 96 weeks in adults failing first-line therapy randomised to raltegravir/lopinavir/ritonavir compared to standard second-line therapy. J Acquir Immune Defic Syndr 2014; 67:161–168. 46. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined && with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised noninferiority trial. Lancet 2014. [Epub ahead of print] Proof-of-concept study demonstrating that in ART-naı¨ve patients, dual therapy was noninferior to triple therapy. There was no substantial difference in safety and tolerability between the two arms; however, dual therapy was virologically less potent in patients with low CD4 counts and high pre-ART viral load. These data suggest that the combination of darunavir/ritonavir once daily plus raltegravir is not as virologically potent as the combination of lopinavir/ritonavir twice daily plus lamivudine. 47. Walensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med 2013; 158:84–92. 48. Engsig FN, Gerstoft J, Helleberg M, et al. Effectiveness of antiretroviral & therapy in individuals who for economic reasons were switched from a once-daily single-tablet regimen to a triple-tablet regimen. J Acquir Immune Defic Syndr 2014; 66:407–413. Interesting study showing that in an advanced healthcare setting in Europe, switching from a branded, single-tablet combination to a generic triple-tablet combination can realize important economic savings with negligible short-term risk of adverse outcomes. &
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