Professional Documents
Culture Documents
clinical therapeutics
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the authors clinical recommendations.
From the Division of HIV/AIDS, Univer- A 52-year-old man with a history of homelessness, depression, and polysubstance
sity of California, San Francisco (UCSF), use received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection
San Francisco (M.G.); and the Division of
Infectious Diseases, Massachusetts Gener- in 2005 but has declined antiretroviral therapy (ART) in the past. His CD4+ T-cell
al Hospital (MGH), Boston, and the Ragon count is now 257 per cubic millimeter, and his plasma HIV-1 RNA level is 17,000 copies
Institute of MGH, Massachusetts Institute per milliliter. The patient was prescribed a multipill antiretroviral regimen 2 months
of Technology, and Harvard, Cambridge,
MA (R.T.G.). Address reprint requests to ago but has not followed this regimen regularly because taking out lots of pills in the
Dr. Monica Gandhi at UCSF, 995 Potrero shelter just announces to the world that I have AIDS [the acquired immunodeficiency
Ave., 4th Fl., San Francisco, CA 94110, or at syndrome]. The patient desires to keep his HIV status private and states that he
monica.gandhi@ucsf.edu; or to Dr. Rajesh
T. Gandhi at MGH, GRB 504, Infectious would take medications regularly if he could take just one pill once a day. The pa-
Diseases, 55 Fruit St., Boston, MA 02114, tient is not taking any other medications; his renal function is normal. How should
or at rgandhi@partners.org. he be evaluated and treated?
*
Drs. Gandhi and Gandhi contributed
equally to this article. The Cl inic a l Probl em
N Engl J Med 2014;371:248-59.
DOI: 10.1056/NEJMct1215532 Effective HIV treatment requires lifelong and daily consumption of multiple anti-
Copyright 2014 Massachusetts Medical Society. retroviral medications. With the advent and refinement of combination ART, the
life expectancy of HIV-infected patients has risen dramatically.1,2 In addition to
benefiting infected persons, ART almost completely blocks HIV-1 transmission to
uninfected sexual partners.3 If we were able to treat most or all HIV-infected pa-
tients and thereby prevent new infections, the beginning of the end of AIDS
would be in sight.4,5
For the benefits of ART to be realized at the individual and population levels,
patients must maintain high levels of adherence to all components of the regimen.
A number of factors are associated with lower levels of adherence,6 including the
stigma associated with HIV infection,7 membership in a minority racial or ethnic
group,8-11 depression,9,12,13 alcohol or drug use,14 cognitive impairment,15 young
age,10 and medication side effects.16 Moreover, rates of adherence to ART may
decline over time,10,12,17-20 even when antiretroviral agents are provided at no cost.
There is therefore a compelling need for strategies that can help patients sustain
lifelong adherence to treatment.
When effective ART was first developed almost two decades ago, adherence
was particularly challenging because patients had to consume handfuls of pills,
often with substantial toxicity, multiple times per day. With the introduction of
coformulated drugs that are less toxic and more potent, there have been dra-
matic reductions in the pill burden. This trend has culminated in single-pill
combinations, in which all components of an ART regimen, typically three or
more medications from two different drug classes, are formulated into one pill
taken once daily.
93.8% to 96.1% (P<0.01), with improvements in ready receiving a stable ART regimen, with viro-
self-reported quality of life. These two studies logic suppression, before making the switch.25,27
probably underestimate the benefit of single-pill Several observational studies, including a pro-
combinations because most participants were al- spective analysis in a cohort of homeless and
Protease
CCR5 coreceptor antagonist inhibitors
HIV-1 Mature
(maraviroc) HIV-1
HIV
protease
8. Budding and
1. Virus Entry Maturation
CCR5 or CXCR4
Fusion inhibitor coreceptor
(enfuvirtide) gp120
gp41
CD4 receptor
Protease
inhibitors
Host cell
Viral
matrix
Nucleus
7. Assembly
Viral
2. Reverse Integrase strand-
capsid
Transcription transfer inhibitors
Viral (INSTIs)
RNA
Viral
Integrase 4. Transcription
Reverse 6. Cleavage
transcriptase Viral Genomic RNA
DNA
3. Integration
Provirus mRNA
Nonnucleoside reverse-
transcriptase inhibitors
(NNRTIs) Protease
Host-cell 5. Translation
DNA inhibitors
Nucleoside and nucleotide
reverse-transcriptase Viral
proteins
inhibitors (NRTIs)
Figure 1. Reproductive Cycle of Human Immunodeficiency Virus Type 1 (HIV-1) and Sites of Action of the Major Classes of Antiretroviral Medications.
Step 1 represents HIV-1 entry into the host cell, which involves the binding of the viral envelope protein, glycoprotein 120 (gp120), to the CD4
molecule, followed by a conformational change in gp120 that allows binding to the chemokine host-cell receptor (e.g., CCR5 or CXCR4). Glyco-
protein 41 (gp41), also part of the virus envelope, then mediates HIV-cell fusion to permit viral entry. The fusion inhibitor, enfuvirtide, blocks
fusion between the virus (through gp41) and the CD4 molecule, and the CCR5 coreceptor antagonist, maraviroc, blocks viral binding (through
gp120) to CCR5. Step 2 is reverse transcription, in which the single-stranded HIV-1 RNA is transcribed into double-stranded DNA by the HIV
enzyme (polymerase) called reverse transcriptase. This step is the site of action of nucleoside and nucleotide reverse-transcriptase inhibitors
(NRTIs) and nonnucleoside reverse-transcriptase inhibitors (NNRTIs). Step 3 is the migration of HIV DNA into the nucleus and its integration
into the DNA of the host cell, a process catalyzed by the viral enzyme integrase. Integrase strand-transfer inhibitors (INSTIs) target this step.
Step 4 is the transcription of the HIV-1 DNA into HIV messenger RNA (mRNA) and HIV genomic RNA. Step 5 is the transport of the HIV-1
RNA out of the nucleus and the translation of HIV-1 mRNA into viral polyproteins. To be functional, the transcribed proteins must be cleaved
into smaller component proteins, a process that occurs in step 6 through the action of the HIV-1 enzyme protease. This is the site of action of
protease inhibitors. Step 7 is the assembly of viral genomic RNA and viral enzymes (reverse transcriptase, integrase, and protease) into viral
particles. Step 8 is the budding and maturation of new viral particles, which then go on to infect other host cells.
hypersensitivity.38 When combined with EFV or responses observed with TDFFTC in patients with
ritonavir-boosted atazanavir, ABC3TC resulted pretherapy HIV-1 RNA levels of 100,000 copies
in inferior virologic responses as compared with per milliliter or higher39,40; this difference was not
observed when the HIV-1 RNA level was less than
100,000 copies per milliliter or when ABC3TC
Use of an SPC for HIV was combined with other agents (e.g., DTG).41-44
Although some clinicians avoid the use of ABC
in patients who are at high risk for cardio-
Is protease inhibitor
Yes
No current SPC available vascular disease because of a putative link be-
based regimen preferred? with a protease inhibitor
tween the drug and myocardial infarction, this
No
finding is controversial45 and has not been
confirmed in other studies, including a meta-
analysis conducted by the Food and Drug Ad-
Is estimated
Do not use SPC
ministration (FDA).46
creatinine clearance Yes
<50 ml/min?
Selection of an Anchor Drug
None of the current single-pill combinations
No
contain protease inhibitors, which should be
used in patients with known viral resistance to
Is patient positive for HLA B5701? Yes Do not use DTGABC3TC NNRTIs or INSTIs. In addition, because trans-
mitted resistance to protease inhibitors is un-
No common and resistance to this class emerges
relatively slowly, protease inhibitors are often
Is HIV-1 RNA level
Yes
SPC options favored when treatment decisions are required
>100,000 copies/ml? EFVTDFFTC (Atripla)
EVGcobicistatTDFFTC
before resistance-testing results are available
(Stribild), if creatinine for example, in the case of patients with acute
No clearance 70 ml/min
DTGABC3TC
HIV-1 infection19 or opportunistic infections.47
Protease inhibitors are also sometimes consid-
SPC options
EFVTDFFTC (Atripla)
ered in patients with inconsistent adherence be-
RPVTDFFTC (Complera) cause multiple viral mutations are required to
EVGcobicistatTDFFTC
(Stribild), if creatinine compromise the activity of these agents. Dis-
clearance 70 ml/min advantages of regimens containing protease in-
DTGABC3TC
hibitors include higher pill burdens (typically
three pills per day) and drug interactions due to
Figure 3. Factors to Consider in the Use of a Single-Pill Combination (SPC) inhibition of the cytochrome P-450 3A4 (CYP3A4)
for the Treatment of HIV Infection. enzyme system by these agents.
For patients who require a protease inhibitorbased regimen, no combination The anchor drug raltegravir does not inhibit
containing a protease inhibitor is currently available as a single pill. In addition,
CYP3A4 activity and has few drugdrug inter-
no combination formulated as a single pill is appropriate for patients with an
actions, with excellent virologic activity.48 Like
estimated creatinine clearance of less than 50 ml per minute, because the
NRTIs (lamivudine [3TC], emtricitabine [FTC], and tenofovir disoproxil fuma- other INSTIs, raltegravir should not be adminis-
rate [TDF]) that are incorporated into single-pill formulations require dose ad- tered with antacids that contain divalent cations;
justments in such patients. In the absence of these constraints, combination these agents can reduce INSTI absorption
therapy administered as a single-pill formulation may be a suitable option. For through chelation. However, unlike other rec-
patients who are positive for HLA B5701 (as determined by host genetic test- ommended anchors, all with once-daily dosing,
ing), the combination of dolutegravir (DTG), abacavir (ABC), and 3TC should raltegravir requires twice-daily dosing 49 and is
not be used. For patients with an HIV-1 RNA level of 100,000 copies per milli- therefore not available in a single-pill combination.
liter or less, any of the single-pill combination regimens may be used. For those
EFV, the anchor drug in EFVTDFFTC, is po-
with an HIV-1 RNA level of more than 100,000 copies per milliliter or with a
CD4+ T-cell count of 200 per cubic millimeter or less, the combination of rilpi-
tent and, in recent years, the drug to which every
virine (RPV), TDF, and FTC should not be used. For patients with a creatinine newly developed anchor antiretroviral agent has
clearance of less than 70 ml per minute, the combination of elvitegravir (EVG), been compared. EFV may cause neuropsychiatric
cobicistat, TDF, and FTC should not be initiated. The DTGABC3TC combina- effects (e.g., vivid dreams, insomnia, somnolence,
tion has not yet been approved as a single pill for clinical use. and depression) or rash, although symptoms
typically diminish over time. The FDA has cate-
gorized EFV as a class D agent with respect to may have a role in patients with virologic suppres-
pregnancy risk on the basis of data from primate sion during treatment with a protease inhibitor
models, although the extent of teratogenicity in containing regimen who have a reason to change
humans is unclear.50-52 According to U.S. guide- medications: in a recent trial, switching such
lines, EFV should be avoided in sexually active patients to RPVTDFFTC maintained high rates
women of reproductive potential who are not of virologic suppression and improved lipid
using contraception, although discontinuing EFV levels.61
if pregnancy occurs is not recommended and EVG, together with the pharmacoenhancer cobi-
EFV is the preferred NNRTI during pregnancy, cistat, is the anchor drug in the single-pill combina-
when initiated 8 weeks after conception.53 The tion EVGcobicistatTDFFTC. This combination
World Health Organization (WHO) recommends was noninferior to two other first-line regimens,
EFV as a first-line agent for women regardless of TDFFTC with either EFV 62-64 or ritonavir-boosted
reproductive potential or pregnancy.54 Finally, atazanavir.65 In the STRATEGY trials, patients
EFV can cause dyslipidemia, although it has not with virologic suppression who were switched
been linked to an increased rate of myocardial from an NNRTI-containing or protease inhibitor
infarction.55 containing regimen to EVGcobicistatTDFFTC
RPV, the anchor drug in RPVTDFFTC, was continued to have high rates of virologic suppres-
approved on the basis of double-blind, double- sion.66,67 Cobicistat-boosted EVG does not have
dummy trials comparing it with EFV, each in neuropsychiatric effects and does not commonly
combination with TDFFTC56 or investigator- cause rash. However, cobicistat inhibits tubular
selected NRTIs.57 The pooled 96-week analysis secretion of creatinine without reducing the cre-
of these studies showed equal rates of virologic atinine clearance. As a result, patients may have
suppression in the RPV and EFV groups.58 The a mild increase in the serum creatinine level, typi-
RPV group had fewer treatment discontinuations cally less than 0.4 mg per deciliter (35 mol per
due to adverse events and lower rates of rash, liter), with this medication initially; if a higher
central nervous system effects, and adverse lipid elevation occurs, evaluation for TDF-induced dam-
effects than the EFV group. Among patients age is warranted. The studies that led to drug
whose pretherapy HIV-1 RNA level was more approval involved patients with an estimated
than 100,000 copies per milliliter or whose creatinine clearance of more than 70 ml per min-
CD4+ T-cell count was less than 200 per cubic ute, so use should be limited to this group.19
millimeter, however, virologic-failure rates were Cobicistat is a potent CYP3A4 inhibitor with po-
higher with RPV. Moreover, among patients with tential drugdrug interactions.
virologic failure, HIV-1 drug resistance muta- DTG is a recently approved INSTI; the recom-
tions emerged more frequently in patients re- mended dose in previously untreated patients
ceiving RPV. In an open-label, randomized study and in previously treated patients who did not
comparing RPVTDFFTC with EFVTDFFTC, receive an INSTI is 50 mg once daily, allowing
each administered as a single-pill combination,59 its potential use in a single-pill combination.
RPV was superior to EFV in patients with pre- Three randomized, phase 3 trials have compared
therapy HIV-1 RNA levels of 100,000 copies per DTG with other first-line agents in previously
milliliter or less and was noninferior to EFV in untreated patients. In the SPRING-2 study, DTG
patients with HIV-1 RNA levels of more than was noninferior to raltegravir when combined with
100,000 copies per milliliter; in patients with vi- either TDFFTC or ABC3TC.42,43 In the SINGLE
ral loads of more than 500,000 copies per milli study, DTG was superior to EFVTDFFTC,68
liter, the rate of virologic failure in the RPV group largely because of more treatment-related dis-
was higher. RPV-based regimens are not recom- continuations with EFV. In the FLAMINGO study,
mended for patients whose pretherapy HIV-1 RNA DTG was superior to ritonavir-boosted darunavir
level is more than 100,000 copies per milliliter or with either TDFFTC or ABC3TC,44 in part be-
whose CD4+ T-cell count is 200 per cubic milli cause of higher rates of study withdrawal in the
meter or less.19 RPV must be taken with a solid darunavir group and lower rates of virologic
meal (390 kcal)60 and requires stomach acid nonresponse among patients in the DTG group
for adequate absorption, precluding the con- who had high viral loads at baseline. DTG was
comitant use of proton-pump inhibitors. In addi- also superior to raltegravir, each given with other
tion to its use in initial therapy, RPVTDFFTC agents, in previously treated patients who had
not received an INSTI,69 and it retains activity is under review at the FDA.73 DTG, like prote-
against some raltegravir-resistant viruses when ase inhibitors, appears to have a high genetic
given twice daily.70,71 A single-pill combination barrier to resistance, which could help prevent
containing DTGABC3TC is pharmacokineti- the development of resistance in patients with
cally bioequivalent to the individual compo- inconsistent adherence; however, more clinical
nents of DTG plus ABC3TC,72 and an applica- experience is needed to assess the role of DTG
tion for approval of the single-pill formulation in this context.
Table 1. Considerations for the Use of Particular Single-Pill Combinations in the Management of HIV-1 Infection.*
Table 1. (Continued.)
* ABC denotes abacavir, DTG dolutegravir, EFV efavirenz, EVG elvitegravir, FDA Food and Drug Administration, FTC emtricitabine, HBV hepatitis B
virus, HIV human immunodeficiency virus, INSTI integrase strand-transfer inhibitor, NNRTI nonnucleoside reverse-transcriptase inhibitor,
QTccorrected QT, RPV rilpivirine, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate, and 3TC lamivudine. To convert the values
forcreatinine to micromoles per liter, multiply by 88.4.
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