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HIV Update -- A Review of the Latest Data With Novel

Antiretroviral Therapies CME


Jose R. Arribas, MD

Faculty and Disclosures


CME Released: 06/23/2014 ; Valid for credit through 06/23/2015

CME Information

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SUMMARY
Antiretroviral therapy (ART) has revolutionized the treatment of patients with HIV; and,
unlike in the 1980s, an HIV diagnosis now constitutes a chronic disease. With many
antiretroviral (ARV) drugs and combinations available, treatment choices are complex.
Various treatment guidelines are available to help clinicians select therapy options for
treatment-naive patients as well as for simplification of therapy and for rescue therapy.
However, because of delays in updating guidelines, clinicians may not be aware of new
developments in ART. The ongoing emergence of HIV drug resistance presents a
challenge to successful use of ART, but this is being countered by the development of new
drugs that attack new targets. More than 20 ART drugs are currently available, categorized
into 6 mechanistic classes: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide
reverse transcriptase inhibitors (NtRTIs), nonnucleoside reverse transcriptase inhibitors
(NNRTIs), ritonavir-boosted protease inhibitors (bPIs or PI/rs), C-C chemokine receptor
antagonists (CCR5s), and integrase strand transfer inhibitors (INSTIs). Each has its own
barrier of resistance, and when resistance develops with an ART regimen, the clinician
needs to switch to a new regimen.
INSTIs are the newest class of agents to become available, and 3 have been approved:
raltegravir, elvitegravir, and dolutegravir. Clinical trial data have established INSTIs as
noninferior to other ARTs, and they are safe and effective in patients with various HIV
subtypes. They have proven to be a good option when switching regimens because of
virologic failure. To date, dolutegravir has not been associated with any drug resistance.
INSTIs have recently all been recommended as treatment options in the US Department of
Health and Human Services (DHHS) guidelines for ART in HIV-1 infected adults and
adolescents, and they are an important addition to the treatment options available to the
clinician.

INTRODUCTION
HIV/AIDS continues to be a significant public health problem. Worldwide, in 2011,
approximately 34 million people were living with HIV, 2.5 million individuals were newly
infected, and there were 1.7 million HIV/AIDS-related deaths.[1]In 2012, an estimated 35.3

million people were HIV-positive. The number of AIDS deaths is in decline, with 1.6 million
deaths in 2012 compared with 2.3 million in 2005 and 3.4 million in 2001.[1]
ART, which has revolutionized HIV treatment, suppresses viral load, thus reducing AIDSrelated morbidity and mortality as well as the risk for transmission. The European AIDS
Clinical Society (EACS) guidelines recommend ART in any HIV-positive person with a
CD4 count <350 cells/L.[2] For individuals with CD4 counts above this level, these
guidelines state that the decision to start ART should be individualized and considered,
especially if a person is requesting ART or has conditions such as HIV-associated kidney
disease, Hodgkin lymphoma, or human papillomavirus-associated cancers. The World
Health Organization (WHO) guidelines recommend initiation of ART as a priority in
individuals with a CD4 count <350 cells/L but also recommend initiation in individuals with
a CD4 count between 350 and 500 cells/L regardless of disease stage.[3] The strongest
recommendation in the DHHS guidelines is for initiating ART in individuals with a CD4
count <350 cells/L, but it also recommends treatment for individuals with higher cell
counts, including those 500 cells/L.[4] The International Antiviral Society (IAS) guidelines
recommend ART for all HIV-positive patients regardless of CD4 count. Most guidelines
recommend early initiation of ART in pregnant HIV patients as well as those with serious
or advanced HIV infection. Although there is some variability among the guidelines overall,
most acknowledge the growing evidence of the benefits of early initiation of ART.[5]
A phase 3 randomized controlled trial enrolled 1763 individuals in 9 different countries with
HIV-1 infection and a serodiscordant partner and assigned 886 patients to early ART and
877 to delayed treatment.[6] Patients needed to have a CD4 count of 350-550 cells/L; 886
patients were randomly assigned to early ART and 877 to delayed treatment (when
patients reached CD4 counts of <250 cells/L). Primary clinical events were defined as
AIDS clinical events and serious medical conditions unrelated to AIDS, including serious
cardiovascular or liver disease. Patients who received early treatment compared with
delayed therapy were less likely to have a primary clinical event (57 vs 77 individuals;
hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.52-1.03; P = .074) and a new-onset
AIDS event (40 vs 61 individuals; HR, 0.64; CI, 0.43-0.96; P = .031). The main difference,
however, was due to extrapulmonary tuberculosis; it is unknown if these results would be
reproducible in the developed world.
A recent study has found that in the developing world many patients are being diagnosed
at a late stage in their HIV infection.[7] Researchers evaluated 334,557 adults who were
receiving HIV care at 132 HIV clinics in Kenya, Mozambique, Rwanda, and Tanzania
between 2006 and 2011. Between these dates, the median CD4 count at ART initiation
increased from 125 to 185 cells/L, an increase of 10 cells/year. In 2011, the odds of a
patient having advanced disease when starting ART were higher among men (adjusted
odds ratio [AOR], 1.4; 95% CI, 1.3-1.5), those on tuberculosis treatment (AOR, 1.6; 95%
CI, 1.3-2.0), and individuals with a 12-month gap or more in pre-ART care (AOR, 2.0; 95%
CI, 1.6-2.6). In developed countries, patients' CD4 counts at first presentation have not
increased over the past 20 years, according to a meta-regression of 197 point estimates
involving CD4 count measurements from 169,007 patients in 44 studies.[8]
The emergence of HIV drug resistance is of increasing concern and represents a hurdle to
the success of ART. Different drugs have different barriers to the development of
resistance. Mutation rates to the drug classes not only differ at baseline but also evolve
over time with exposure to ART. In the event of drug resistance, with confirmed virologic
failure, clinicians should promptly switch a patient's regimen. More than 20 approved ART

drugs in 6 mechanistic classes are available for use in combination regimens (Table 1).
The 6 classes are NRTIs, NtRTIs, NNRTIs, bPIs or PI/rs, CCR5s, and INSTIs.
Table 1. The 6 Mechanistic Classes of Antiretroviral Therapy

Nucleoside reverse
transcriptase inhibitors
[NRTIs]

Abacavir [ABC], didanosine [ddI], emtricitabine [FTC],


lamivudine [3TC], stavudine [d4T], and zidovudine [AZT]

Nucleotide reverse
transcriptase inhibitors
[NtRTIs]

Tenofovir [TDF]

Nonnucleoside reverse
transcriptase inhibitors
[NNRTIs]

Efavirenz [EFV], etravirine [ETV], nevirapine [NVP],


rilpivirine [RLP]

Ritonavir-boosted
protease inhibitors [bPIs
or PI/rs]

Atazanavir + ritonavir [ATV/r], darunavir + ritonavir


[DRV/r], fosamprenavir + ritonavir [FPV/r], indinavir +
ritonavir [IDV/r], lopinavir/ritonavir [LPV/r], saquinavir +
ritonavir [SQV/r])

C-C chemokine receptor


antagonists [CCR5s]

Maraviroc [MVC]

Integrase strand transfer


inhibitors [INSTIs]

Raltegravir (RAL), elvitegravir [EVG], dolutegravir [DTG]

The WHO, DHHS, IAS, and EACS produce guidelines for the clinical management of HIV
infection and describe how the different regimens should be used.[2-4,9]
The most recent class of drugs to be developed is INSTIs. The HIV integrase enzyme
catalyzes the irreversible integration of the HIV reverse transcribed viral DNA into the host
genome through 2 successive catalytic reactions called 3' processing and strand
transfer.[10] All 3 approved drugs specifically target the second step of the integration
process through pi-stacking with the long terminal repeats that are located at both
extremities of reverse transcribed HIV DNA molecules and through coordinating Mg2+ ions
that are necessary for integration.[10] Three INSTIs have been licensed for use as ART.
Raltegravir was approved in 2007 as a twice-daily INSTI and is recommended in various
guidelines. In the last few months, 2 new INSTIs, elvitegravir and dolutegravir, have been
approved and included in recommended ART regimens in the recently updated DHHS
guidelines. They are also expected to be included in the other guidelines.
Raltegravir is usually administered with tenofovir and emtricitabine, although it can also be
used with abacavir and lamivudine. Dolutegravir can be administered with tenofovir and
emtricitabine. In the United States, dolutegravir is also administered with abacavir and
lamivudine. It is expected that the single-pill formulation of dolutegravir will soon be

available. Elvitegravir is available in a quad pill, a once-daily single-tablet regimen also


containing the novel pharmacoenhancer cobicistat (a CYP3A4 inhibitor that boosts levels
of other drugs but has no antiviral activity itself), and with tenofovir/emtricitabine.

RESISTANCE PATTERNS WITH OLD AND NEW DRUGS


The use of highly active ART in patients with HIV can lead to the development of drug
resistance, which can cause therapeutic failure, an increase in the transmission of resistant
virus, and a decrease in therapeutic options and survival. Clinicians should test patients for
drug resistance prior to starting therapy with most classes of drugs and then regularly monitor
them for indications of the development of drug resistance.[2-4]

Overview of Resistance
The future efficacy of drugs or drug classes can be affected by resistance that emerged
previously, as HIV drug-resistant strains are archived in cellular reservoirs.[10] An updated list of
surveillance drug resistance mutations has identified 93 mutations, including 34 NRTIresistance mutations at 15 reverse transcriptase (RT) positions, 19 NNRTI-resistance
mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease
positions.[11] Current guidelines recommend switching to a new therapeutic regimen when
virologic failure is confirmed,[3,9] but the guidelines differ on the best approach to managing
treatment-resistant patients.
The WHO recommends that second-line ART consists of a ritonavir-bPI plus 2 NRTIs when
NNRTI-containing regimens were used in the frontline setting.[3] The IAS recommends
switching to a PI combined with an INSTI or a CCR5 antagonist (if tropism test shows R5 virus
only) in cases of NRTI/NNRTI failure. For NRTI/bPI failures, because mutations to PIs are
uncommon, alternative regimens may include replacing the 2 NRTIs with an approved or
investigational INSTI.[4] According to the EACS, in general, any regimen should use at least 1
fully active PI/r plus 1 drug from a class not used previously (eg, fusion, integrase, or CCR5
antagonist) or 1 NNRTI, assessed by genotypic testing.[2]

Drug Resistance With INSTIs


Novel drugs are being developed to address the problem of drug-resistant HIV strains, with the
newest class of therapeutics being INSTIs. A subgroup analysis of 699 HIV patients with tripleclass drug resistance in the BENCHMARK-1 and BENCHMARK-2 trials showed that raltegravir
is active in HIV patients with triple-class drug resistance.[12] A case study demonstrated that the
combination of dolutegravir and peginterferon alfa-2a achieved long-term control of HIV
replication in a man with sextuple-class resistance.[13]

The principles of INSTI resistance parallel those of NRTI, NNRTI, and PI resistance -resistance is caused by primary mutations, and the development of secondary mutations
further decreases virus susceptibility to treatment.[14] In addition, the genetic barrier to INSTI
resistance is defined by the number of mutations required for the loss of clinical INSTI activity.
There is extensive but incomplete cross-resistance among the INSTIs.[14] Data from clinical
trials and other investigations show that because primary integrase mutations are rare,
resistance testing is not needed before starting therapy with this class of agents. Studies
estimate that fewer than 0.1% of INSTI-naive individuals harbor viruses with primary INSTI
resistance mutations.[14] Raltegravir and elvitegravir are susceptible to the emergence of drug
resistance, whereas dolutegravir is associated with a higher barrier to resistance (Table 2).[12,1522]

Table 2. Mutations Detected in Treatment-Naive Patients Progressing on INSTI Therapy


Major Resistance Mutations Minor Resistance Mutations
RAL Y143
N155H
Q148

Multiple

EVG T66I
E92Q
N155H
Q148

Multiple

DTG None

None

DTG = dolutegravir; EVG = elvitegravir; RAL = raltegravir


Data from Cooper DA, et al[12]; Sichtig N, et al[16]; Canducci F, et al[17]; Hatano H, et al[18]; Sax
PE, et al[19]; DeJesus E, et al[20]; Walmsley SL, et al[21]; Feinberg J, et al. ICAAC 2013. Abstract
H-1464.
Dolutegravir is the only INSTI that has not, to date, been associated with de novo emergence
of resistance mutations in treatment-naive individuals. Several clinical trials provide evidence of
dolutegravir's ability to evade the development of resistance. In the FLAMINGO trial, which
evaluated dolutegravir against darunavir/ritonavir in 484 ARV-naive adults, none of the patients
who received either regimen developed treatment-resistant mutations.[22] No antiviral resistance
to dolutegravir was detected in the 414 patients who received dolutegravir in the SINGLE study
(Study ING114467).[21]

In another analysis of 1222 treatment-naive patients who received first-line therapy with
dolutegravir, no individuals developed resistance against the compound after 48-96 weeks of
follow-up.[23] In previously treatment-experienced patients who received dolutegravir as a firsttime integrase inhibitor as a component of a second-line regimen, clinicians documented only 4
virologic failures with resistance mutations. The R263K integrase resistance mutation was
observed in 2 of these 4 instances. In in vitro studies, dolutegravir-resistant viruses were
impaired in their ability to acquire further resistance to lamivudine and nevirapine because of
the inability of the virus to develop resistance mutations associated with these 2 compounds.[23]
Raltegravir and elvitegravir show extensive cross-resistance and should not be used
sequentially.[15] Raltegravir and elvitegravir-resistant strains show variable levels of crossresistance to dolutegravir, which can partially be overcome by doubling the dose of dolutegravir
to twice daily and ensuring the presence of other active drugs in an ARV regimen.[15] In VIKING
3, if a baseline genotype did not harbor the Q148 integrase resistance mutation and the
background regimen had an overall susceptibility score of 1, then the proportion of patients
with HIV-RNA <50 copies/mL at week 24 was 88%.[24] The development of viral resistance to
elvitegravir may occur when it is coadministered with drugs that interact with elvitegravir and
cobicistat via induction of CYP3A activity.[25]
A study examining integrase genotypic resistant tests performed on 3012 patients at a national
referral laboratory in the United States from 2009 to 2012 found that 471 (15.6%) had viruses
with 1 or more raltegravir- or elvitegravir-resistant mutations. The Q148 and N155 pathways
were equally represented (197 patients each), and 84 patients had Y143 mutations. Q148
rarely occurred without accessory mutations (n=3). High-level dolutegravir resistance was
predicted in 12% of patients with raltegravir- or elvitegravir-resistant viruses. The authors
concluded that dolutegravir is likely to have full or partial activity in patients progressing on 1 of
the other 2 INSTIs.[26]
The current DHHS guidelines recommend that in HIV-positive patients not responding to
INSTI-based regimens, a genotypic assay for INSTI resistance should be performed to
determine whether to include a drug from this class in subsequent regimens.[4]

ART IN TREATMENT-NAIVE HIV PATIENTS


Guideline Recommendations
According to the 2013 WHO guidelines, the recommended choice for first-line therapy in HIV
patients is a once-daily regimen comprising 2 nonthymidine NRTIs (either tenofovir and
emtricitabine or tenofovir and lamivudine) and 1 NNRTI (efavirenz) as a fixed-dose

combination.[3] The IAS recommendations, most recently updated in 2012, continue to be


based on a combination of 2 NRTIs/NtRTIs (eg, tenofovir/emtricitabine or abacavir/lamivudine)
and a potent third agent, generally an NNRTI (eg, efavirenz), a PI/r (eg, atazanavir or
darunavir), an INSTI (eg, raltegravir), or, rarely, an agent that blocks the CCR5.[9] The 2013
EACS guidelines recommend combining the NRTIs abacavir and lamivudine or tenofovir and
emtricitabine with either efavirenz or rilpivirine, a PI/r (atazanavir or darunavir), or raltegravir
(Table 3).[2] The guidelines also suggest alternative regimens that can be used in patients who
may not be suited to the recommended ones.
Table 3. EACS-Recommended Regimens for Treatment-Naive HIV Patients: A Drug From
Column A Should Be Combined With the Drugs Listed in Column B
A

Remarks

NNRTI NRTI
EFV
RPV

ABC/3TC ABC/3TC coformulated


or
TDF/FTC coformulated
TDF/FTC EFV/TDF/FTC coformulated
RPV/TDF/FTC coformulated

PI/r
ATV/r
DRV/r

ABC/3TC ATV/r: 300/100 mg qd


or
DRV/r: 800/100 mg qd
TDF/FTC

INSTI
RAL

TDF/FTC RAL: 400 mg bid


or
ABC/3TC

3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; bid = twice daily; DRV/r =
darunavir/ritonavir; EFV = efavirenz; FTC = emtricitabine; INSTI = integrase strand transfer
inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse
transcriptase inhibitor; PI = protease inhibitor; qd = once daily; RAL = raltegravir; RPV =
rilpivirine; TDF = tenofovir disoproxil fumarate
Data from EACS Guidelines.[2]

The DHHS guidelines are the most recently updated; they were revised in May 2014.[4] These
guidelines continue to recommend several regimens for ARV-naive patients (Table 4): 1
NNRTI-based regimen comprising efavirenz/tenofovir disoproxil fumarate/emtricitabine; 2 PIbased regimens comprising ritonavir-boosted atazanavir + tenofovir disoproxil
fumarate/emtricitabine or ritonavir-boosted darunavir + tenofovir disoproxil
fumarate/emtricitabine; and the INSTI-based regimen of raltegravir 400 mg twice daily plus
tenofovir 300 mg/emtricitabine 200 mg once daily. As part of the update, these regimens were
changed from preferred to recommended, and an additional 3 INSTI-based regimens have
been included, bringing the total to 4 (Table 4): elvitegravir 150 mg/cobicistat 150 mg/tenofovir
300 mg/emtricitabine 200 mg once daily in patients with estimated creatinine clearance (CrCl)
70 mL/min (EVG/COBI/TDF/FTC). This regimen was previously considered an alternative
regimen. Two dolutegravir-based regimens are now also recommended: dolutegravir 50 mg
once daily plus abacavir 600 mg/lamivudine 300 mg once daily in patients who are HLA
B*5701 negative; and dolutegravir 50 mg once daily plus tenofovir 300 mg/emtricitabine 200
mg once daily. A number of alternative regimens are also provided (Table 4).
Table 4. DHHS Guidelines Recommended First-line Regimens in Treatment-Naive
Patients
Recommended Regimens for ART-Naive patients Regardless of Baseline Viral Load or
CD4 Count
NNRTI-Based Regimen

EFV/TDF/FTCa

PI-Based Regimens

ATV/r + TDF/FTCa
DRV/r + TDF/FTCa

INSTI-Based Regimens

RAL + TDF/FTCa
EVG +COBI+TDF +FTC
DTG +ABC/3TCa
DTG +TDF/FTC

Recommended Regimens for Patients With Pre-ART Plasma HIV RNA <100,000
copies/mL
NNRTI-Based Regimens

EFV + ABC/3TCa -- only for patients who are HLA-B*5701 negative


RPV +TDF/FTCa -- only for patients with CD4 cell count >200 cells/mm3

PI-Based Regimen

ATV/r + ABC/3TCa -- only for patients who are HLA-B*5701 negative

Alternative Initial ART Regimen Options


These are regimens that are effective and tolerable but have potential disadvantages when
compared with the recommended regimens or have less data from randomized clinical trials.
An alternative regimen may be the preferred regimen for some patients.
PI-Based Regimens

DRV/r + ABC/3TCa -- only for patients who are HLA-B*5701 negative


LPV/r (onceb or twice daily) + ABC/3TCa -- only for patients who are HLA-B*5701
negative
LPV/r (onceb or twice daily) + TDF/FTCa

INSTI-Based Regimen

RAL + ABC/3TC -- only for patients who are HLA-B*5701 negative

Data from DHHS.[4]


a

3TC can be substituted for FTC or vice versa. The following combinations in the

recommended list above are available as coformulated fixed-dose combinations: ABC/3TC,


EFV/TDF/FTC, EVG/COBI/TDF/FTC, LPV/r, RPV/TDF/FTC, and TDF/FTC.
b

Once-daily LPV/r is not recommended for pregnant patients.

3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ATV/r = atazanavir/ritonavir;


COBI = cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG =
elvitegravir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; LPV/r
lopinavir/ritonavir; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside
reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; TDF
= tenofovir disoproxil fumarate
When selecting the most appropriate regimen for a patient, clinicians should take into
consideration any drug-related, disease-related, and patient-related factors. Selection of a
regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing
frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions.
Some of the older regimens are effective but have large pill burdens, and a high pill burden has
been shown to be a predictor of nonadherence.[27,28]

INSTIs Offer New Options


The 3 new INSTIs offer new options for treatment-naive patients. Each regimen has different
characteristics, including dosing frequency, number of tablets per day, and whether medication
needs to be taken with a meal (Table 5).
Table 5. Comparison of 4 INSTI-Based Regimens
RAL +
TDF/FTC

EVG/COBI/TDF/FTC DTG +
ABC/3TC

DTG +
TDF/FTC

Dosing frequency

Twice daily

Once daily

Once daily

Once daily

Numbers of tablets
per day

Meal consideration

None

Take with a meal

None

None

Data from http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf


3TC = lamivudine; ABC = abacavir; COBI = cobicistat; DTG = dolutegravir; EVG = elvitegravir;
FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; RAL = raltegravir; TDF =
tenofovir disoproxil fumarate

Effectiveness of INSTIs
For the most part, INSTIs were approved after being shown to be noninferior to other preferred
ART regimens in treatment-naive patients. The noninferiority double-blind STARTMRK trial
enrolled 566 patients who had a viral load of >5000 copies/mL and susceptibility to
efavirenz.[29,30] At baseline, 53% of patients had a viral load of <100,000 copies/mL, and 47%
had a CD4 count of 200 cells/mm3 or less. Participants were randomly assigned to receive
either 400 mg raltegravir twice daily or 600 mg efavirenz once daily. Both groups received
300/200 mg tenofovir/emtricitabine once daily. In a 48-week noncompletion-equals-failure
analysis, 86.1% of patients in the raltegravir arm and 81.9% in the efavirenz arm achieved a
viral load of <50 copies/mL. In the primary noncompleter-equals-failure efficacy analysis at
week 240, 71.0% of patients receiving raltegravir and 61.3% of patients receiving efavirenz had
HIV RNA levels <50 copies/mL. In Protocol 004, an initial dose-ranging trial comparing
raltegravir vs efavirenz with tenofovir/lamivudine, similar virologic and immunologic results at
week 48 were observed as in STARTMRK.[31]
The phase 3 GS-US-236-0102 trial involved 700 treatment-naive patients with an HIV viral load
of at least 5000 copies/mL and susceptibility to efavirenz.[19] Patients were randomly assigned

to elvitegravir or coformulated efavirenz 600 mg, emtricitabine 200 mg, and tenofovir 300 mg.
The study showed noninferiority, with 87.6% of patients in the elvitegravir arm and 84.1% of
patients in the control arm having HIV RNA concentrations <50 copies/mL at week 48
(difference, 3.6%; 95% CI, 1.6%-8.8%).[19] The phase 3 GS-236-0103 study enrolled 715
treatment-naive patients with an HIV viral load of 5000 copies/mL and susceptibility to
atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned to receive
EVG/COBI/FTC/TDF or atazanavir/ritonavir + emtricitabine/tenofovir (ATV/RTV + FTC/TDF)
plus matching placebos once daily. Results in 708 treated patients found that
EVG/COBI/FTC/TDF was noninferior to ATV/RTV+FTC/TDF for the primary outcome (89.5%
vs 86.8%, HIV RNA concentration 50 copies/mL after 48 weeks, respectively; adjusted
difference 3.0; 95% CI, -1.9% to 7.8%). Safety and tolerability findings were favorable with both
regimens.[20]
In the SINGLE trial, 833 treatment-naive patients who had an HIV-1 RNA level of 1000
copies/mL were blindly randomly assigned to receive either dolutegravir 50 mg with fixed-dose
abacavir sulfate and lamivudine once daily or fixed-dose efavirenz/emtricitabine/tenofovir once
daily.[21] At week 48, the dolutegravir regimen showed superiority with more patients receiving
this novel INSTI regimen achieving an HIV-1 RNA level of <50 copies/mL(88% vs 81%; P=
.003).
The SPRING-1 trial randomly assigned 205 treatment-naive adults to receive dolutegravir 10,
25, or 50 mg once daily or efavirenz 600 mg once daily combined with either
tenofovir/emtricitabine or abacavir/lamivudine.[32] At week 96, the proportion of participants
achieving plasma HIV-1 RNA <50 copies/mL was 79%, 78%, and 88% for dolutegravir 10, 25,
and 50 mg, respectively, compared with 72% for the control arm. The median increase from
baseline in CD4 cells was 338 cells/mL with the novel INSTI (all treatment groups combined)
compared with 301 cells/mL in the control arm (P = .155).
The FLAMINGO trial was conducted in 484 treatment-naive patients with HIV-1 RNA of at least
1000 copies/mL and no primary RT/protease mutations. Patients were randomly assigned to
once-daily dolutegravir 50 mg or once-daily ritonavir-boosted darunavir 800/100 mg with
investigator-selected tenofovir/emtricitabine or abacavir/lamivudine, stratified by HIV RNA
(/>100,000 copies/mL) and NRTI. At week 48, a greater percentage of patients receiving
dolutegravir had achieved a viral load of <50 copies/mL (90% vs 83%; P = .025).[22]
The SPRING-2 trial evaluated 827 treatment-naive patients who had HIV-1 RNA
concentrations of 1000 copies/mL.[33] At week 96, once-daily dolutegravir was noninferior to
twice-daily raltegravir in terms of achieving an HIV-1 RNA <50 copies/mL. The authors

concluded that once-daily dosing without requirement for a pharmacokinetic booster made
dolutegravir-based therapy a very promising therapeutic option.

Adverse Events With INSTIs


Overall, INSTIs are well-tolerated and have very few side effects;[34] however, all 3 are
associated with an increased risk for nausea and diarrhea. Raltegravir is associated with a risk
for skin rash with fever (rare), creatine phosphokinase elevation, muscle weakness,
rhabdomyolysis (very rare), transient elevation of serum transaminase levels, hypersensitive
reactions, and hepatitis.[4,29,30] Elvitegravir has been shown to increase the risk for headache,
insomnia, and estimated glomerular filtration rate (GFR) decreases when it is combined with
cobicistat.[4,19] Patients taking dolutegravir or cobicistat experience only benign elevations in
serum creatinine because these drugs inhibit tubular creatinine secretion without influencing
the actual GFR.[35]
Discontinuation of INSTI treatment because of adverse events is a rare occurrence. In the
STARTMRK trial, the discontinuation rate was 5% in patients taking raltegravir.[29,30] In the
SINGLE trial, the rate was 2% in the dolutegravir arm.[21] In GS-US-236-0102, the rate for
discontinuation of elvitegravir was 4% in patients receiving the single quad pill.[19]

Special Considerations for Choosing an ART Regimen


Special considerations are advised for patients with certain comorbidities and characteristics
when choosing an ART regimen for HIV-infected patients (Table 6, Table 7, Table 8). For
example, tenofovir should be used with caution in patients with renal
insufficiency.[4] EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl
<70 mL/min per the US label and <90 per the EU label and should be changed to an
alternative regimen if the patient's CrCl falls below 50 mL/min.[2,4,19] Abacavir should be used
with caution in patients with a known high risk for cardiovascular disease.[4] Since 2008, when
the increased risk for myocardial infarction with abacavir became established, the use of this
regimen in HIV patients has been declining, but a recent study showed that there continues to
be an association between abacavir use and myocardial infarction risk.[36]
High viral load is another factor to consider when >100,000 copies/mL.[4] Clinicians are advised
to review the details of the clinical trials that led to approval of the INSTIs to determine which
regimen might be best for their patients. Evidence from the SPRING-1 and SPRING-2 trials
supports the use of dolutegravir in patients regardless of baseline viral load[32,33] Rilpivirine is
only recommended in patients who have a viral load <100,000 copies/mL.[37]

Results from some studies suggest that certain patients might benefit from first-line use of
INSTIs. For example, INSTIs are a good option for patients with cardiovascular disease
because of their small impact on lipid levels. Patients with multiple comorbidities requiring
multiple medications are also good candidates for raltegravir and dolutegravir. The 2 newer
INSTIs are not substrates for CYP3A; therefore, the risk for drug-drug interactions is low.[38] On
the other hand, cobicistat is a potent CYP3A4 inhibitor and may therefore interact with various
drugs, so EVG/COBI/TDF/FTC is not a good option for patients with multiple comorbidities and
polypharmacy.[4] Viral resistance to elvitegravir may develop if the drug is coadministered with
drugs that interact with elvitegravir and cobicistat via induction of CYP3A activity.[25]
Other special considerations include the presence of HLA-B*5701 and the rate of creatinine
clearance (Table 6, Table 7).
Table 6. Special Characteristics to Consider When Selecting an INSTI Regimen
RAL +
TDF/FTC

EVG/COBI/TDF/FTC

DTG +
ABC/3TC

DTG +
TDF/FTC

No

Yes

No

No

COBI-potent CYP3A4
inhibitor

DTG-minor
CYP3A4
substrate

DTG-minor
CYP3A4
substrate

Should not be started in


patients with CrCl <70
mL/min and should be
changed to an alternative
regimen if the patient's
CrCl falls below 50 mL/min

Dosage
adjustment
for 3TC if
CrCl <50
mL/min

Dosage
adjustment for
TDF and FTC
if CrCl <50
mL/min

HLA-B*5701 (+) No concern


patients

No concern

Do not use
this regimen

No concern

Other
considerations

Should not be used with


other ARV drugs or with
nephrotoxic drugs

CY 3A4
interactions

EVG-CYP3A4 substrate
CrCl and
dosing

Dosage
adjustment for
TDF and FTC
if CrCl <50
mL/min

Should be
used with
caution in
patients with
renal
insufficiency.

Should be
used with
caution in
patients with
renal
insufficiency.

Data from http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf


3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; COBI = cobicistat; CrCl = creatinine

clearance; DTG = dolutegravir; EVG = elvitegravir; FTC = emtricitabine; INSTI = integrase


strand transfer inhibitor; RAL = raltegravir; TDF = tenofovir disoproxil fumarate
Table 7. Special Characteristics to Consider When Selecting Recommended Non-INSTI
Regimens
NNRTI-Based Regimen

EFV/TDF/FTC*

Comments

EFV is teratogenic in nonhuman primates. A non-EFV


regimen should be strongly considered in women who
might become or are planning to become pregnant.

TDF should be used with caution in patients with renal


insufficiency.
ATV/r should not be used in patients who require >20 mg
omeprazole equivalent per day.

PI-Based Regimens

ATV/r + TDF/FTC*
DRV/r (once daily) +
TDF/FTC*

Source: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
*3TC may substitute for FTC or vice versa. The following combinations in the recommended
list above are available as coformulated fixed-dose combinations: ABC/3TC, EFV/TDF/FTC,
EVG/COBI/TDF/FTC, LPV/r, RPV/TDF/FTC, TDF/FTC, and ZDV/3TC.
3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; COBI = cobicistat; DRV/r =
darunavir/ritonavir; EFV = efavirenz; EVG = elvitegravir; FTC = emtricitabine; INSTI = integrase
strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse
transcriptase inhibitor; PI = protease inhibitor; RPV = rilpivirine; TDF = tenofovir disoproxil
fumarate; ZDV = zidovudine
In summary, all 3 INSTIs are recommended for HIV treatment-naive patients in the DHHS
guidelines. EVG/COBI/TDF/FTC is only approved for patients with a creatinine clearance >70
mL/min, and cobicistat is a potent CYP3A4 inhibitor. Dolutegravir has been shown to be
noninferior to raltegravir and can be given once daily with or without food; however,
postmarketing experience with the drug is limited

SIMPLIFICATION THERAPY
Overview

In some cases, patients may request simplification of therapy to improve their quality of life. A
recent study reported that 48% of patients wished to simplify their regimen, 20% were
concerned about long-term side effects of their current regimen, 14% had trouble tolerating the
current regimen due to side effects, and 5% had trouble taking their current regimen on a
regular basis.[39] In other cases, clinicians may suggest simplification to minimize drug side
effects, maintain long-term adherence, and reduce the risk for virologic failure.
Clinicians might consider simplifying regimens for patients who are taking older drugs that are
associated with more severe side effects and that often come with a high pill burden and/or
frequent dosing requirements.[4] In one study, a pill burden of more vs less than 10 pills per day
was associated with a much higher risk for nonadherence than twice- vs once-daily dosing or
small differences in the number of types of ARV treatments in a regimen.[27]
Adherence to anti-HIV medications has been shown to increase with reduced dosing
frequency. A meta-analysis of 11 randomized clinical trials involving 3029 patients revealed
that the adherence rate was improved in patients who received once-daily regimens vs with
twice-daily regimens (+2.9%; 95% CI, 1.0%-4.8%; P < .003).[40] Treatments currently available
in once-daily dosing include efavirenz, didanosine, tenofovir, lamivudine, atazanavir,
emtricitabine, elvitegravir, and dolutegravir. Caution is needed when choosing a simplified
regimen, as not all simplification efforts will result in the maintenance of virologic suppression.
Clinicians can choose to simplify therapy with drugs from the currently used class of drugs or
from a different class. The randomized Nevirapine, Efavirenz and Abacavir Resistance Team
trial compared nevirapine, efavirenz, or abacavir as substitutes for protease inhibitors in 460
HIV-1-infected patients successfully treated with ARV regimens containing protease inhibitors - patients had viral load <200 copies/mL for the previous 6 months.[41] With 36 months of followup, virologic failure occurred more frequently in patients switched to abacavir than in patients
switched to efavirenz or nevirapine. In individuals with previous suboptimal treatment with
mono- and dual-NRTIs, the risk for treatment failure was particularly high. This study and
others highlight the need for clinicians to consider the potential for drug resistance before
simplification. A boosted PI should be switched to unboosted (atazanavir), an NNRTI, or
raltegravir only if the full activity of the 2 NRTIs (or other agents) remaining in the regimen can
be guaranteed.[2,4]Authors of the SWITCHMRK trials, in which patients with suppressed viremia
who were taking a lopinavir-ritonavir-based regimen were randomly assigned to stay on their
regimen or switch to raltegravir, concluded that clinicians need to gather all available
background information on past resistance tests and treatment outcomes in order to guarantee

the activity of the 2 NRTIs when contemplating the potential risks and benefits of
simplification.[42]
High lipid value is a common reason for simplification. The phase 3 SPIRIT trial evaluated
simplifying a regimen of a protease inhibitor/ritonavir plus 2 NRTIs to a regimen of
rilpivirine/emtricitabine/tenofovir in 317 patients who were switched compared with 159 patients
who were not switched.[43] Patients who switched continued to have an undetectable viral load
and an improved lipid profile associated with lower cardiovascular risk (low-density lipoprotein
cholesterol, -16 vs 0 mg/dL; triglycerides, -53 vs +3 mg/dL).

Simplification With INSTIs


Good tolerability and fewer drug interactions than with other ARTs make simplifying therapy
with INSTIs an attractive option. Rates of diarrhea are low with dolutegravir, raltegravir,
elvitegravir, and rilpivirine/tenofovir/emtricitabine.[19,21,29,30,43]
In some cases, switching to INSTIs can result in lower lipid levels. Early results from the
STRATEGY-PI study have demonstrated that regimen simplification from a PI-based regimen
(PI+ RTV +FTC/TDF) to the single tablet containing elvitegravir maintains HIV suppression and
is well-tolerated.[44, 45]
To be included in the study, patients had to be receiving their first or second ARV regimen and
have a viral load of <50 copies/mL for at least 6 months with no prior virologic failure or preexisting resistance. At 48 weeks of follow-up, patients who switched (n=290) were more likely
to have HIV-RNA <50 copies/mL than those who did not switch (n=139) (94% vs 87%; 95% CI,
0.4-13.7; P = .025). There was a larger decrease from baseline in fasting triglycerides for
patients receiving the quad pill (median: -16 vs +3 mg/dL; P = .001). Patients switching from
lopinavir/ritonavir had the largest decreases in total cholesterol, low-density lipoprotein, and
triglycerides. Only 7% of patients taking EVG/COBI/TDF/FTC had diarrhea.
STRATEGY-NNRTI was a simplification study conducted in patients receiving an NNRTI
regimen (NNRTI + FTC/TDF) who had a viral load <50 copies/mL for at least 6 months. In the
trial, 290 patients were randomly assigned to the single tablet EVG/COBI/TDF/FTC and 143
patients to stay on current therapy.[39,46] The study demonstrated that elvitegravir was
noninferior to the NNRTI regimen in maintaining virologic suppression (HIV-1 RNA <50
copies/mL) at week 48. Patients who switched therapies had small decreases in total
cholesterol (-8 vs 3; P = .010), low-density lipoprotein (-4 vs 5; P = .001), and high-density

lipoprotein (0 vs -3; P = .008). Only 8% of patients taking EVG/COBI/TDF/FTC regimen had


diarrhea.
The SWITCHMRK-1 and 2 double-blind, randomized trials included 707 eligible patients who
were randomly assigned to switch from lopinavir-ritonavir to raltegravir (n=353) or to remain on
lopinavir-ritonavir (n=354), while continuing background therapy consisting of at least 2 NRTIs
or NtRTIs.[42] To be included, patients had to have documented viral RNA concentration below
the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based
regimen. Although switching to raltegravir was associated with greater reductions in serum lipid
concentrations, efficacy data did not establish noninferiority of raltegravir to lopinavir-ritonavir.
No patients receiving raltegravir had moderate to severe diarrhea. Failures in patients taking
raltegravir were concentrated in patients who had experienced prior virologic failures, and the
researchers suggested that these patients probably had partially active nucleosides. To date,
there are no clinical trials testing dolutegravir in patients wishing to simplify therapy.

RESCUE TREATMENT
Overview
It is estimated that up to one quarter of patients receiving ART are not virologically suppressed
and are therefore not achieving target plasma HIV RNA levels.[47] Some patients may have
minimal or no drug resistance, whereas others may have extensive resistance, depending on
their treatment history. Management of virologic failure and extensive resistance is a complex
process, but strategies are available to manage such cases. Assessing and managing failure
of ART is complex. The DHHS guidelines make several recommendations for rescue
treatment.[4] A new regimen should include at least 2 (preferably 3) fully active agents, whose
expected activity is based on the patient's treatment history, drug-resistance testing, and/or the
drug's novel mechanism of action. The guidelines do not recommend adding a single, fully
active ARV drug to a virologically failing regimen because of the risk for rapid development of
resistance to all drugs in the regimen. However, in certain cases, the combination of a fully
active ritonavir-boosted PI and a single active drug may result in a regimen that is as effective
as a regimen with more active agents. Such active ARV agents include etravirine, darunavir,
tipranavir, and dolutegravir, as well as drugs with a unique mechanism of action, such as the
CCR5 antagonist maraviroc. Some ARVs such as darunavir and dolutegravir may need to be
administered twice rather than once daily in order to achieve higher drug concentrations for
patients with preexistent protease or integrase mutations. The DHHS guidelines make several
other recommendations for rescue treatment (Table 8).

Table 8. DHHS Recommendations for Rescue Treatment

Assessing and managing an HIV patient experiencing treatment failure is complex.


Clinicians should seek expert advice.
Evaluation of virologic failure should include an assessment of adherence, drug-drug or
drug-food interactions, drug tolerability, ART history, use of concomitant medications with
consideration of adverse drug interactions with ARV agents, HIV RNA and CD4 T-cell
count trends over time, and prior and current drug-resistance testing results.
Drug-resistance testing should be performed while the patient is taking the failing ARV
regimen or within 4 weeks of treatment discontinuation. Even if more than 4 weeks have
elapsed since the ARVs were discontinued, resistance testing can still provide useful
information to guide therapy, though it may not detect previously selected resistance
mutations.
The goal of treatment for ARV-experienced patients with drug resistance who are
experiencing virologic failure is to establish virologic suppression
A new regimen should include at least 2, preferably 3, fully active agents. A fully active
agent is one that is expected to have ARV activity on the basis of a patient's treatment
history and drug-resistance testing results and/or the drug's novel mechanism of action.
In general, adding a single fully active ARV agent to a virologically failing regimen is not
recommended because of the risk for development of resistance to all drugs in the
regimen.
For some highly ART-experienced patients, maximal virologic suppression is not
possible. In this case, ART should be continued with regimens designed to minimize
toxicity, preserve CD4 cell counts, and at least delay clinical progression.
When no viable suppressive regimen can be constructed for a patient with multidrugresistant HIV, the clinician should consider enrolling the patient in a clinical trial of
investigational agents or contacting pharmaceutical sponsors that may have
investigational agents available.
Discontinuing or briefly interrupting therapy in a patient may lead to a rapid increase in
HIV RNA and a decrease in CD4 cell count and increases the risk for clinical
progression. Therefore, this strategy is not recommended.

Data from http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf


ART = antiretroviral therapy; ARV = antiretroviral

INSTIs in Rescue Treatment


Good tolerability and fewer drug interactions make INSTIs an attractive choice when switching
treatment regimens due to virologic failure. Several clinical trials have tested INSTIs in HIV
rescue therapy.
Raltegravir has achieved positive results as a second-line therapy in clinical trials. The
BENCHMARK study enrolled triple-class resistant HIV patients who were not responding to
therapy and who were INSTI-naive.[48] Patients received either placebo (n=237) or raltegravir
(n=462). At week 240, the viral load was <50 copies/ mL in 42% of the patients who were
initially assigned to raltegravir and <400 copies/mL in 210 (45%); virologic failure occurred in
36% of patients who received raltegravir during the double-blind phase and 6% of patients

during the open-label phase. The phase 2 TRIO trial enrolled 103 patients with HIV RNA levels
>1000 copies/mL who did not respond to therapy on NNRTIs, had 3 or more PPI and NRTI
mutations, and had 3 or more darunavir and NNRTI mutations.[49] Patients received raltegravir
plus etravirine and darunavir/ritonavir. At week 48, a total of 86% of patients had an HIV RNA
level <50 copies/mL.
The EARNEST and SECOND-LINE studies tested different regimens in patients not
responding to 2 nucleos(t)ides plus an NNRTI. EARNEST (n=1277) sought to evaluate any
incremental benefit of adding NRTIs or raltegravir to a boosted PI backbone for second-line
therapy. The study compared lopinavir/ritonavir plus NRTIs vs 2 other regimens -lopinavir/ritonavir monotherapy following a raltegravir induction and lopinavir/ritonavir plus
raltegravir -- and found that lopinavir/ritonavir plus raltegravir was noninferior to
lopinavir/ritonavir plus NRTIs. The authors concluded that the PI NRTI regimen should be
made more widely available.[50] The SECOND-LINE study (n=558) demonstrated that a
regimen of lopinavir/ritonavir and raltegravir was as effective as a regimen containing
lopinavir/ritonavir and 2 or 3 nucleoside or nucleotide analogs as second-line therapy in
patients who were not responding to HIV therapy.[51]
The phase 3 GS-US-183-0145 trial enrolled patients who had plasma HIV RNA of 1000
copies/mL or greater, any CD4 cell count, and resistance to or 6 months of experience with at
least 2 classes of ARV drugs.[52] The study found that 59% of 351 patients who received
elvitegravir achieved virologic response compared with 58% of 351 who received raltegravir
(treatment difference, 1.1%; 95% CI, 6.0-8.2), meeting the criterion for noninferiority (P = .001).
Three patients who received elvitegravir had serious drug-related adverse events compared
with 7 patients who received raltegravir; 2 and 8 patients died, respectively.
Clinical trial data suggest that dolutegravir might be the most effective INSTI in rescue therapy.
The phase 3 SAILING study enrolled patients who were naive to INSTI, had 2 consecutive
plasma HIV-1 RNA assessments of 400 copies/mL or higher (unless >1000 copies/mL at
screening), resistance to 2 or more classes of ARV drugs, and 1-2 fully active drugs for
background therapy.[53] Patients were randomly assigned to receive once-daily dolutegravir 50
mg (n=354) or twice-daily raltegravir 400 mg (n=361), with investigator-selected background
therapy. At 48 weeks, more patients receiving dolutegravir had a viral load <50 copies/mL than
did patients receiving raltegravir (71% vs 64%; 95% CI, 0.7-14.2; P = .03). Significantly fewer
patients receiving dolutegravir had virologic failure with treatment-emergent integrase-inhibitor
resistance (4 vs 17 patients; P = .003).

In the single-arm VIKING trial, dolutegravir twice daily was given to patients who were resistant
to raltegravir and/or elvitegravir as well as multiple other drug classes.[24,54] At week 24, a total
of 69% of the 183 patients who received raltegravir had achieved a viral load <50 copies/mL.
At week 48, a total of 56% had a viral load <50 copies/mL. Of the 114 patients who had
reached week 48 at the time results were evaluated, 56% had achieved a viral load <50
copies/mL.
The EACS and DHHS guidelines recommend INSTIs for rescue therapy.[2,4]

CONCLUSION
There is strong evidence showing the effectiveness of all 3 INSTIs in treatment-naive patients
with HIV, treatment-experienced patients, and those with multiple drug class resistance. All are
recommended in the DHHS guidelines for treatment-naive patients. In rescue therapy,
dolutegravir is the INSTI supported by the strongest evidence to date. It is the only ARV drug
not yet associated with de novo emergence of resistance mutations in treatment-naive
individuals and has demonstrated efficacy in patients who are resistant to elvitegravir and
raltegravir.
In addition to their effectiveness and resistance profiles, the 3 INSTIs are attractive treatment
options due to good tolerability and low pill count. Raltegravir and dolutegravir are associated
with fewer drug-drug interactions. Elvitegravir is available as a single-tablet treatment that can
be taken without food. Raltegravir was the first approved INSTI and, therefore, has been used
longest in the community. The INSTIs are an important addition to the treatment
armamentarium against HIV infection.

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