-Students must not plagiarize text from the papers provided (avoiding excessive quotations), nor should you cut and paste text from websites or other sources. HIV drug resistance: problems and perspectives and perspectives Pleuni s. Pennings Department of Biology, Stanford University, CA, UsA health. [thtectious Disease Reports 2013: 5sles] [page 24] feriew European patients with transmitted drug limited settings, Stadeli and Richman found half- lives. Efoetive monotheeagy is mest likely resistance whe were treated with a fally artive that 7\% of patients who have been on ART for to occur in patients on NNETI-hased treatcombination of drugs, 95s had fully s.p. 6.11 months had resistasoe, 114 after 12.23 metts, because NNRTIs typically hane longer pressed viral Wad afler one year. of the months and 21N after 36 months of more.' A half tives than NKTls." Howerer, the impor patients who were trealod with an insulficient- similar effect has been reported for patients in tance of effective monotherapy for mesistance Vy strong regimen, k.W had fully suppressed high incoeme couatries. For example, a large is debaled. "ln low income countries, there is viral lnad after one year. stady from the IK meports that the percentage concern alout resistance doe to unplanned In low-income couatries, patients with of putients with at least one drug-resistance treaament interruptions when patients are transmitted drug resistance may start insaff- mutation increases from 11 to 14 to 15s after faced with stock-osts at the bospital or pharciently strong ART regimens, because viral fout, six and eight years respectively for macy. For example, Mareellio ed " "show that genotpping is usualy not available and trans. patients on NNRTL-bsed treatment.' This treatment interruptions occur in Camserwon mitted resistance not delected. Insulficienlly stady shows that even a patient whose viral doe to drug shortages in hospitals. strong treatments will be less effective i i population did not exhe resistance during six reducing the viral bod, which, in turn, can lead years of treatiment has a peokability of around to the evolution of multi class drug resistance. ZN to acquire resistance during the next year In addition, even if testing is done, fener sec- of treatsent. ond lise trealment options are wailable for In general, treatments based on NNRTls or patients in low-income countries. unboosted Pls are more susceptible to resist. Multi-chass drug resistanoe typically occurs ance than treatment based on a ritonaic- when a virus that is resistant to ose drod boosted PI (bPI)." bPI regimens are less sus acquires resistance to another drug. In prindAcquired drug resistance ceplible to resistance, parth because resist- ple, it is possible that a vinis acquires muliple ance to the bll itself is unlikely to evolve, bet dres-resishoce mutations at the samse time. during antiretroviral treatment also because, in the prosence of the hPl, it is but data sagsest that this is uncommon. F.

1. -Students must not plagiarize text from the papers provided (avoiding excessive quotations), nor
should you cut and paste text from websites or other sources. HIV drug resistance: problems and
perspectives and perspectives Pleuni s. Pennings Department of Biology, Stanford University,
CA, UsA health. [thtectious Disease Reports 2013: 5sles] [page 24]
feriew European patients with transmitted drug limited settings, Stadeli and Richman found half-
lives. Efoetive monotheeagy is mest likely resistance whe were treated with a fally artive that
7% of patients who have been on ART for to occur in patients on NNETI-hased
treatcombination of drugs, 95s had fully s.p. 6.11 months had resistasoe, 114 after 12.23 metts,
because NNRTIs typically hane longer pressed viral Wad afler one year. of the months and 21N
after 36 months of more.' A half tives than NKTls." Howerer, the impor patients who were
trealod with an insulficient- similar effect has been reported for patients in tance of effective
monotherapy for mesistance Vy strong regimen, k.W had fully suppressed high incoeme
couatries. For example, a large is debaled. "ln low income countries, there is viral lnad after one
year. stady from the IK meports that the percentage concern alout resistance doe to unplanned In
low-income couatries, patients with of putients with at least one drug-resistance treaament
interruptions when patients are transmitted drug resistance may start insaff- mutation increases
from 11 to 14 to 15s after faced with stock-osts at the bospital or pharciently strong ART
regimens, because viral fout, six and eight years respectively for macy. For example, Mareellio
ed " "show that genotpping is usualy not available and trans. patients on NNRTL-bsed treatment.'
This treatment interruptions occur in Camserwon mitted resistance not delected. Insulficienlly
stady shows that even a patient whose viral doe to drug shortages in hospitals. strong treatments
will be less effective i i population did not exhe resistance during six reducing the viral bod,
which, in turn, can lead years of treatiment has a peokability of around to the evolution of multi
class drug resistance. ZN to acquire resistance during the next year In addition, even if testing is
done, fener sec- of treatsent. ond lise trealment options are wailable for In general, treatments
based on NNRTls or patients in low-income countries. unboosted Pls are more susceptible to
resist. Multi-chass drug resistanoe typically occurs ance than treatment based on a ritonaic- when
a virus that is resistant to ose drod boosted PI (bPI)." bPI regimens are less sus acquires
resistance to another drug. In prindAcquired drug resistance ceplible to resistance, parth because
resist- ple, it is possible that a vinis acquires muliple ance to the bll itself is unlikely to evolve,
bet dres-resishoce mutations at the samse time. during antiretroviral treatment also because, in
the prosence of the hPl, it is but data sagsest that this is uncommon. For. unlikely that resistance
evolves to the other example, Harrigan ef of," having analyed Since 1996, standard treatment of
IEV has drugs the patien is taking (es. NRTls). This dau from a large Canadian cohset,

2. demoncosisted of a cembination of three drups in protective effect of the bri can be explained, in
state that at any ese time, there are more prisciple, masy combination can be created part, by the
low plasma viral loads achiered on patients with drug resistance to one chass of from the bogs
list of antiretrowital drugs that bPls. However, Kempl te al." showed that NKTI drags than
patients with resistance to more are on the market. In practice, only a few com- resistance is
enlikely to evolve even in than one drus, which is consistent with resist. Binations are used for
most patients and rec- patieats with viremia (unsuppressed virs) ance ecoking one mutation at a
time. On the cmmended as firt-line treatment for treat- when they are taking a bP. The
mechanism other hand, data reviewed by Stadeli and meos-nahe patients. The most common
com- behind this obsenation is not yed understood Richinan seggest that in resouroe-limited
se:Benation therapy eosists of an NNRT and two NNRT- bused NRT is more common in low-
tings, multi-class trug resistanee is more comNKThs, which is available as a see-pill-a-day
income countries than in high-income coun- mon and arvond thee-equarters of patients
treatment. Also common in high-income coun- tries, which means that there is a relatively with
at least some resistanoe have multidass tries is the combination of a protease inhibitor high risk
of drug resistance in low income drug resistance. This difference may be due to (PI) with two
NRTls. This combination is only countries. In addition, if a patient's virus lack of monitoring in
resouree-limited set. used as second line therapy (Wben standard eceires drog resistance en
NNKT-based ART, tings." Unfortunately, data on multi-dass dreg drugs fall) in low-income
countries and not it is less problematic in high-iscomecountries pesistance and the effect of
moniloring are availatle as a one-pill-way resimen. In onfer because it will be fisconered faster
due to res searce, but the general belief is that switching. to make Pl-baced treatment as effective
as ular viral load monisorisg and viral genotypieg, quickly after detection of the first drug-resist.
NNRTI-based treatment, the Bood levels of the so that the patient can be switched to second-
ance mulation can prevent the accumulation PI need to be increased by adding a small dose line
treatment when necessary. of further drus-resistance mutations. If treatof another protease
inhibitor (ritonavir). There is a strong association between ment is continued even though coce of
the which is eallod boosting Nocadas, boosted pi acquired drug resistance aod sub-optimal drogs
so logger works, the virus will likely repimes art more common than unboosted P1 adherence to
the treatment regimen. For ewolve resistabe to the other drugs. regimets. Recently, a thirl option
has been example, Lima ed al." show that drut resist- The Phate II study showed that, in Europe,
added to the list of recommended combina- ance is more than twice as common in patients the
peralence of patients who had falled on all tions for treatment naive individuals: two with 80-965
adherence when compared to three major drus dasses (NRTI, NNBTI and NRTIs combined witt
an integrase strand patients with adherence levels of 95% or high- FI) increased steadily alter
1996, bet remained transfer inhililor (LSSTI). This combination is ef. It is clearly documented

3. that structured stable from 2016 onwards.". This is probably also a milable as a one-pila-day
regimen. The Ireatment interruptions lead to drug resist- because the incidence of multichass
resist. evolution of drug resistaece of these combint. ance (es. Danel at af. 2009), lu likely
because ance went downh, which, in tum, can be attribtion treatments is moch less liliely than
the an intemuption allows for growth of the viral uted to imperrements in monitoriag, simpler
evolution of dnig resishase on tratasents population and leads to a higher abendance of and less
toxic regimens, which led to betser consisting of just one or two drugs, as were resistance
matations. When treatment is start- adherence, and betier pharmacodynamies, common in the
late 1980 and the first half of od again, these resistance mutations ean which made regimes more
robrst to sub-optithe 1990s. Still, drug resistance can exobe dur. quickly rise in froquency and
kad to failume it mal odheremoe. While be risk of multi-dass ing treatment. It serms plausile that
noe wherene leads to drog resistance went down. be chances of Te dearest pattere of acquired
drug resist- drus resistance in exactly same way, In addi- suceessful treatmeat for patients with
multi. ance in patients on ART is that the peroentage tion, sub-optimal adbernne can lead to per-
class resistant virus improved ower the last of patieats with drup resistance goes up ods of
effective monotherapy (the presence of decade." This impeorement is mainly doe to sieadily with
time on treatment. For example. just one drug above the minimally effective the fact that several
new drogs entered the in a meth-analysis of studies from resource- concentration) when drugs
have very different market, svch as raliegravir (INSTI) and [page 22] [Infectious Disease Reports
2013; 5sie5]
many resistance mutations and an uncommon plest option, which is no longer recummended,
esen if a matation is present at bieth enoobh combination of three or more drugs needs to is to
use nevirapine (NVP, an NNiti). Asingle frequenc to be delerlet, thete in no gatatee be used, this
is relemed to as sahage therapy. Gose of nevirapine (saNVP) meduces the prober that it will kad
to rirulopic hallure Ooe neasm bility that the child is inferted perinatally, but fur this may be that
even though the mutation despite sevirapise, In a meta andysis, Artive sufficientle douthet, yet
antrated posilility For a long time there were only three main of at: 3 found that on average 36%
of the is that the locitioe of origit af the detected NRTh, NNRTIs and Pis. The drups witlin
resistance several weeks after the treatment whether a nipority rariast iscetese of treatment on
one NNRTL, it was unlikely thut with sdNVP are more likrly to fail therapy I I stand under
which circamatasos minarive treatment with another would work." From they are later treated
with NNKTI based ART " swiants lead to trathent fillire. 2000 multiple new drugs from old and
new. For bese nomen, il is lether to shet with Miosrity uriants can boob be delected but it CCES
antagonists (earawiroc) and fusion due to the combination of monotherapy with a tions can te
determinet to guide treatnest inhibiters (enfunirtide). There are laspe difterences between the

4. genetics of resistance to different drugs, and tions. The situation is somewhat belter if derisions a
mutrion with higher alentasce than women are treated with the NRTI ridowudine this Filue
inficates at increaced rist of treatthe tew dasses are to exception. for example. integrase inhibitors
mallemeavir and ehile-. of the inteprase gene can make the virus hish. resistasce is alse reduced
if NvP monotherapy ly resistant against raltegravir. The resistance is awoided by adding a so-
called NRTI twil, ie, early with the alemoner of a ner mesistat profile of ehitegewir is simitar,
and motations a combination of twe NRTh (ZDV and 3TC C for bif value man itill be detrraised
dependitg on at position 148 and 155 were also otserned in patients who thiled irratment with the
soad piil, a one pillided regimen that coetins cobicistat boosted elvitegravir and two gained from
preverted fillus. cobicistat boosted elvitegravir and two NRThs." The fosion inhibitor enfurirtide
has they are not eligille for treatment for their ure due to miovite wariants withoot hocwing. been
aailable since 2000, but is not used as which patients carry then, by notifing the fint-line threapy,
sartly because it has to be way trealment is stariod. For eunple, treat injected subcutaneonaly.
Sereral mutations ment could be starled wiith a set of inass that are knowe to conder resistance to
eaflunitide." are not susrepilile on ing nesitance (ex- a Resistanoe against the CCRS antagonist
marResistance againt the CcCS antaponist marbPf hused cundination) asd cnce the viral had
avinc comes in two distind flavors. Either, the virus can accumulate mutations that allow it to use
inhibitor bound CCR5, of the virus can in the patient (around 20 frequency or tipy switch
tropiam and use CXCR4 instead of CCRS as a co-receptor to enter the cella The er). In recent
years, boweve, stuties have latser is moee contmen becase CXCR4-asing geency variants (dews
to 0.18 frequence. formelated ose pilladxy retinea. Soch a variants can be present at relatively
Migh frequencies even priar to tratment with a CCRS depending on the assar). The presence of
such modified start of treatment moy be acerptalle inbibitec A recent study based on dees.
sequencing bound CXCRA-using variants in ated with an increased risk of virulopic fallare. not
needed. more than 90 of patients, though at yery low frequencies in mayy of them, H peession of
viral replication, oue to resist- chosse a repinen for pre treated patients. For ance." From an
erolutionary penpective, this ecample, the peesence of luwabendunce is entirely expecied If the
mutation that coo- NNKT mutatives in wumes whe were posifers resistance is already present in
the patient wasty treated fice FMTCT, predicted treatnent Prevention of mother-to-child befure
tratment starts, such mutation may failure when thry started Nvxnthased akr:" transmission
increase in frequency rapidy after the start of Fisher ef al ased a deep setuencing aqponach optn
acciss [lnfections Disease Reports 2013; 5:sle5] [page 23]
Revien