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There have been many reports of the transmission of
drug-resistant strains of HIV. While studies from the
late 1990s suggested that less than 10% of new
infections involve drug-resistant virus, recent studies
suggest that many seroconverters are infected with a
type of HIV that has reduced sensitivity to at least one
anti-HIV drug. As the uptake of antiretroviral therapy
has spread, so has the transmission of drug-resistant
strains.
How
many people are initially infected with resistant virus?
Dr John Mellors told the 1999 Resistance Workshop that
about 3% of newly infected patients have virus resistant
to the nucleoside analogues and/or protease inhibitors,
and that 7% have NNRTI-resistant HIV. Canadian, British
and Swiss data from the late 1990s confirmed these
relatively low estimates (Alexander 1999; Williams 1998;
Pillay 2000; Yerly 1999-2001).
However, this work has been superseded. A growing body
of research suggests approximtely 8-30% of people who
contract HIV in Europe or the United States will acquire
a virus with drug-resistant mutations.
The large European study known as CATCH involved 1633
newly infected people in Europe (excluding France and
Britain) between 1996-2002. Overall, primary resistance
mutations were detected in 9.6% of the group. By drug
class, mutations associated with resistance to NRTIs
were seen in 6.9% of participants, to NNRTIs in 2.6%,
and to PIs in 2.2% (van der Vijver 2003).
In the United States, several studies have shown a
significant increase in the proportion of newly infected
patients with a drug resistant strain of HIV. For
example, a study of seroconverters in ten cities between
1995-2000 found the prevalence of resistance mutations
increased from 8% to 23%, while the proportion of
recently infected people with multidrug resistant virus
rose from 4% to 10%. Phenotypic resistance data showed
that over 12% of newly infected people had high level
resistance to at least one drug in 1999-2000 (Little
2002).
Another study conducted in five US cities has found an
increase in drug-resistance among newly infected people
(Bennett 2002), and a study of 281 people commencing
treatment at 100 sites in the US found evidence of
resistance in 8.9% (Becker 2002).
A San Francisco study has also found that more people
are contracting a drug-resistant strain of HIV. By
2000-2001, 13% of seroconverters had a virus resistant
to non-nucleoside reverse transcriptase inhibitors (NNRTIs)
and 8% were resistant to protease inhibitors (PIs).
Interestingly, the prevalence of resistance to the NRTIs
fell from 21% to 6% (Grant 2002).
A New York study has confirmed this decline in the
prevalence of NRTI resistance among recently infected
people (from 8% in 1995-1998 to 3% in 1999-2001),
attributing this shift to a fall in the number of people
with 3TC resistance. However, this decline was offset by
an increasing number of people with PI and NNRTI
resistance. By 1999-2001, nearly 20% were infected with
virus which showed resistance mutations to NNRTIs and
PIs; 8% had phenotypic resistance to NNRTIs and 5% had
resistance to PIs (Simon 2002).
Other European data also indicate that many newly
infected people have a drug-resistant form of HIV:
 In
the United Kingdom, 27% of people who contract HIV in
2000 were infected with drug-resistant virus. From
1994-2000, 14% of seroconverters had resistant virus (UK
Collaborative Group 2001).
Preliminary
data from the SPREAD study involving five European
countries show that 9% of 348 recently infected people
in 2002-03 had a virus which contained primary mutations
(Wensing 2003).
In
Berlin between 1996-1999, 13% of 54 seroconverters were
infected with drug-resistant virus, although resistance
was generally weak (Duwe 2001). In 2002, 16% of
seroconverters had resistant virus and a multidrug
resistant virus was first detected in a seroconverter (Kucherer
2003).
Prevalence
of drug-resistant mutations among treatment-naive
Spaniards was 17% for NRTIs and 6% for PIs in 1998 (Puig
2000).
Another
Spanish study found an even higher incidence of drug
resistance mutations in recent 30 seroconverters between
1997-1999; 24% had NRTI-related mutations and 7% had
primary PI resistance mutations (Briones 2001).
Most
recently, Spanish researchers reported a signficantly
reduced level of drug-resistant mutations among newly
infected people in 2000-2001 compared to 1997-1998
(Mendoza 2002).
A
French study of 108 seroconverters identified during
1999 found 6.5% had NRTI resistant HIV, 3.7% with NNRTI
resistance and 2.8% with PI resistance (Chaix).
In
Belgian in the 1990s, 27-31% of newly infected people
had at least one genotypic resistance mutation (van
Vaerenbergh 2001).
In
Switzerland, 11% of people with primary HIV infection
between 1996-1998 had resistance to at least one
anti-HIV drug, and trends suggested the proportion of
newly infected individuals infected with a
drug-resistant form of HIV fell during 1998-2000
compared to 1996-1997 (Yerly 1999-2001).
In
Poland, 6.25% of treatment-naive patients were infected
with virus which contained primary resistance mutations
(Bielawski 2003).
In Brazil, the prevalence of drug resistance among
untreated HIV-infected people is quite low, with only
about 2% showing resistance to each of the three drug
classes (Brindeiro 2003).
The data point to considerable variation over time and
by location in the proportion of newly infected people
with drug-resistant virus. Improvements in prescribing
practices may be reducing the pool of people with
drug-resistant virus, which may lead to further
reductions in the number of people becoming infected
with resistant virus. Alternatively, the ongoing
existence of resistant virus and risk behaviours in some
HIV-positive populations may lead to a stable or
increasing proportion of people seroconverting with
drug-resistant HIV.
Is
the proportion of seroconverters with drug-resistant
forms of HIV increasing?
Two recent studies indicate the answer is 'it seems so',
although there is conflicting evidence. The UK
Collaborative Group on Monitoring Transmission of HIV
Drug Resistance reported a significant increase in the
proportion of newly infected people who have contracted
a resistant strain of HIV in 2000-2001. A large US study
of 377 seroconverters from ten cities has reported that
more people are contracting drug-resistant HIV. In
1995-1998, only 3.4% of seroconverters had resistant
virus compared to 12.4% in 1999-2000 (Little 2002).
However, there is other evidence which contradicts the
notion of a gradual rise in transmission of
drug-resistant HIV. Swiss research found that 1997 was
the peak year for transmission of drug-resistant virus,
suggesting that better control of viremia over time and
greater attention to the need for adherence may have
reduced the risk (Yerly 2001). Genotypic resistance was
detectable in 4% of seroconverters in 2000, compared to
14.6% in 1997 and 8.6% in 1996. Similarly, a study of
209 recent US seronverters tested between 1997 and 1999
found no increase in incidence of drug resistance in
treatment-naive individuals over time, but also no
decline (Weinstock 2000).
The most recent US study, carried out between June 2000
and March 2002, found no significant increase in
transmitted drug resistance when this period was
compared with 1995-1998 and 1998-2000. Indeed, NRTI and
PI resistance in seroconverters declined significantly
when 2000-2002 was compared with 1998-2000, with much of
the resistance detected in the 2000-2002 period
attributable to NNRTI resistance. Multidrug resistance
declined significantly, from 6.5% to 0.8% (Little
2002b).
As described in the section above, two other US studies
have found evidence that the prevalence of NRTI
resistance among seroconverters is falling (Simon 2002;
Grant 2002). In San Francisco, the prevalence of
PI-associated mutations remained steady from 1996 to
2001, although the prevalence of NNRTI-associated
mutations increased (Grant 2002).
French surveillance of seroconverters failed to detect
any increase in drug resistance in the period 1999-2000
compared with 1996-1998 in 251 individuals. Resistance
was found in 10% of patients. of whom half had
resistance to more than one class of antiretroviral (Harzic
2002).
In Montreal, Canada, a decline in resistance amongst
newly infected individuals has been noted since 2000,
and this is significantly correlated with the proportion
of patients receiving antiretroviral treatment (Routy
2002).
Screening of seroconverters entering a study of primary
infection at St Mary's Hospital in London found no
evidence of drug resistance in 15 individuals screened
during 2000 and 2001 (the same period during which the
UK Collaborative Group was finding an increase in the
proportion of seroconverters with drug resistant virus,
suggesting that in the UK at least, the transmission of
drug resistant virus may be concentrated in particular
cities.
While the evidence is somewhat equivocal, an editorial
in the British Medical Journal has confirmed the
seriousness of recent trends showing a greater
proportion of people are contracting drug-resistant HIV.
It identifies the urgency of improved drug adherence and
targeted prevention messages to reduce the risk of
transmission of drug-resistant HIV (Little 2001).
Transmission
of NRTI-resistant virus
Initial reports about the transmission of drug-resistant
HIV concerned resistance to the class of drugs known as
nucleoside analogues or NRTIs. Swiss researchers tested
for AZT-resistant HIV in 60 people with seroconversion
illness. Although the number of cases was small,
transmission of AZT-resistant strains appeared to be
becoming more common. Swiss researchers have calculated
that between 1991 and 1994, around 10% of new infections
involved AZT-resistant virus.
Australian researchers also suggested a 10% rate of
transmission of resistant virus. In 1996, researchers in
Edinburgh reported that two of 35 British people who
became infected with HIV after 1990 had been infected
with AZT-resistant strains. In Seville, the proportion
of treatment-naive people found to be harbouring
AZT-resistant strains has increased from nil in
1989-1990, to 11% in 1991-1992, 15% in 1993-1994 and 42%
in 1995-1996.
Since those early days of AZT monotherapy, virus which
is resistant to several nucleosides has been
transmitted. Recent US figures show the proportion of
newly infected people who have a NRTI-resistant virus
rose from 3% in the mid-1990s to 8% 1999-2000 (Little
2002).
Transmission
of PI-resistant virus
US researchers documented a case of transmission of
virus with reduced susceptibility to AZT, 3TC, ddC and
all protease inhibitors in 1998 (Hecht). Another case
was identified in which a subject with viral load of
approximately 1 million copies passed on a virus with
AZT and PI-associated resistance mutations during anal
intercourse, even without ejaculation (Boden).
Furthermore, a case report about a baby who contracted a
multi-drug resistant strain of HIV from its mother was
presented at the 1999 Retroviruses Conference in
Chicago.
In 1998 Swiss researchers reported that 5% of those
identified as seroconverters during the 1996-98 period
had acquired HIV with protease resistance mutations.
There has also been one report of the transmission of a
multi-NRTI, multi-protease resistant virus in the United
States.
Recent US data showed that the proportion of people
contracting PI-resistant virus rose from less than 1% in
1996-1998 to 8% 1999-2000 (Little 2002).
Transmission
of NNRTI-resistant virus
Recent estimates of the rates of transmission of NNRTI-resistant
virus generated controversy at the 1999 International
Workshop on HIV Drug Resistance. A team from the US
reported that 22% of recent seroconverters had
phenotypic resistance (reduced sensitivity) to NNRTIs.
However, nearly half this group had no evidence of
genotypic changes associated with NNRTI resistance, and
several experts suggested that far from indicating
widespread transmission of NNRTI resistant virus, these
findings indicated widespread natural variation in
sensitivity to NNRTIs of minimal clinical relevance (Boden).
A 1998 study of treatment-naive patients at London's
Royal Free Hospital also reported at this meeting found
that most genotypic changes associated with NNRTIs were
secondary mutations that do not confer high level
resistance on their own. These findings suggest that
NNRTI-resistant virus may be transmitted rarely (Loveday).
Retrospective testing of plasma samples stored during
the 1980s has shown that virus isolates from drug naive
individuals had reduced NNRTI senssitivity, suggesting
that there is large natural variation in NNRTI
sensitivity (Paxinos). Subsequent research into rates of
NNRTI-resistant virus among newly infected individuals
has taken these natural variations into account.
There is a trend indicating that transmission of NNRTI-resistant
virus is becoming more common in the US. Rates of NNRTI-resistant
virus were about 1% in 1996-1998 and rose to 7% in
1999-2000 (Little 2002). A study of 225 people with
recent HIV infection who presented to the San Francisco
General Hospital between June 1996 and June 2001 found
that the overall prevalence of resistant strains in
2000/2001 was 27.4%, similar to the 25% prevalence found
in 1996/1997. However, while the prevalence of PI- and
NRTI-resistant virus remained fairly stable over time,
the prevalence of NNRTI-related resistance rose from 0%
to 13.2% over the same period, and resistance to two
drug classes increased concomitantly (Grant 2002).
Resistance
in genital fluids
Resistance testing usually measures drug resistant HIV
in the plasma. However, HIV also exists in lymph tissue,
the genital tract and fluids, and the brain.
There is some evidence that resistance mutations in the
blood plasma correlate with mutations in the lymph
tissue. In contrast, there is strong evidence that
resistance in the blood does not necessarily mean
resistance in the genital tract. For example, a study of
resistance mutations from blood and cervicovaginal
lavage of two women found that response to therapy and
resistance mutations differed in the two compartments (Eron;
Fang). In addition, two men treated during primary
infection had resistant virus in their blood, but
undetectable virus in their semen (DePasquale 1999).
However, drug resistant HIV has been detected in the
genital tract (Hazelwood 1999). This case study
confirmed that protease inhibitor mutations not present
in the blood may appear in the genital tract. Thus
localised replication can lead to the development of
resistance in the genital compartment. Whilst NRTIs such
as AZT and 3TC may be present in much higher
concentrations in semen than in blood (Periera),
protease inhibitors do not always appear to reach
adequate concentrations in semen (Taylor).
Transmission
of drug resistant HIV by different routes
A study of 21 recently infected injecting drug users and
56 individuals who contracted HIV through sexual
activity found no difference in the rate of
transmission, suggesting no difference in the
transmissability of drug-resistant viruses by blood or
by sexual intercourse (Salomon 2000).
Resistance
and reduced infectiousness
Although between 3-25% of seroconverters in countries
with widespread access to antiretrovirals have
contracted drug resistant HIV, there is emerging
evidence that resistant virus is less infectious. A
study comparing the frequency of transmission of
resistant virus with the prevalence of resistance among
the HIV-positive community suggested that resistant
virus has only a 25% capacity to infect others compared
to wild-type virus (Leigh Brown 2003).
However, a study of 11 partner pairs carried out in San
Francisco suggests that in each cases where transmission
of drug resistant viruses took place, all the resistance
mutations detected in the index case persisted in the
infected patients (Hecht).
Implications
of infection with drug resistant HIV
Just because a person has predominantly drug-resistant
strains in their blood does not mean that someone they
infect will receive a drug-resistant strain. Even people
with highly drug-resistant HIV strains usually also have
wild-type strains in their pool of viruses, and it is
possible that these are more transmissible. HIV strains
found in semen may also be wild-type even when those in
the blood are drug-resistant, and vice versa.
Transmission of drug-resistant virus has implications
for the effectiveness of antiretroviral treatment. A
recent study found that 26% of seroconverters had
reduced susceptibility to at least one anti-HIV drug,
although high-level drug resistance was uncommon (Little
1999).
There is not yet conclusive evidence to determine if
people infected with resistant strains have a different
prognosis than people with wild-type virus. In people
who are not taking anti-HIV drugs, some resistant
strains disappear to undetectable levels in the body
over time and are replaced by wild-type ones. However,
several studies have shown that people who acquire a
drug-resistant form of HIV do not necessarily 'revert'
to wild-type virus.
For example, AZT-resistant virus can persist for at
least fourteen months after infection if it carries the
codon 215 mutation.
An analysis of people in Southern California has shown
that specific drug resistance mutations may persist for
at least one year after the estimated date of infection.
Six patients with the K103N mutation associated with
NNRTI resistance were shown to have this mutation more
than one year after infection, suggesting that drug
resistance testing may be useful in individuals up to
one year after the estimated date of infection (Little
1999). The persistence of NNRTI resistance may have
implications for secondary transmission of resistance;
if resistant virus persists for more than a year, it is
possible that a large proportion of drug-resistant new
infections could be generated by highly infectious
individuals who have already acquired drug resistant
virus, and who are experiencing acute HIV infection.
A study of four individuals who acquired multidrug
resistant (MDR) HIV found that resistance persisted for
up to five years. Although acquisition of the MDR virus
resulted in lower levels HIV in the blood when compared
to patients with wild-type virus, HIV levels rose in two
cases when the 3TC-associated M184V mutation disappeared
(Brenner 2002). The study also found that whilst the
mutant virus disappeared within 12 weeks of removing
drug pressure (by treatment interruption) in the source
partners, MDR HIV persisted in partners with primary HIV
infection.
Canadian researchers have suggested that some
individuals may take a very long time to develop
wild-type virus (Chan 2003). They have made the claim
based on two case studies in which resistant virus
persisted for three years in untreated patients, while
the two sources of the resistant virus experienced
reversion to wild-type virus when they stopped therapy.
The absence of a wild-type reservoir was thought to
explain the persistance of the resistant virus.
It is also possible that resistant strains are made less
harmful to the immune system by their mutations than
wild-type strains. However, transmission-acquired
resistance does not appear to influence the rate of
disease progression. A survey of 101 UK seroconverters
found no evidence of a slower rate of disease
progression (measured as time from estimated
seroconversion date to a CD4 cell count of 350 cells/mm3)
(Pillay 2002). Canadian researchers have in fact linked
drug-resistant virus to faster disease progression (Chan
2003).
San Francisco researchers have produced contradictory
findings to the UK Seroconverter group. They identified
130 seroconverters diagnosed since 1996, and found that
those with genotypic evidence of drug resistance or
virus with reduced replication capacity had
significantly higher CD4 cell counts (p=0.02; p=0.04
respectively) after controlling for duration of
infection (Grant 2002).
Superinfection
Superinfection is re-infection of an HIV-positive person
with a slightly different version or strain of HIV. This
new version of HIV may be drug-resistant. Although for
many years considered a theoretical possibility, several
case reports strongly suggest that superinfection does
occur.
The first case of superinfection was reported by Dr
Anders Sonnenborg at the Glasgow Conference Drug Therapy
in HIV Infection in late 1998. In November 1998 a man
presented with acute retroviral syndrome following
multiple unprotected sexual encounters. At that time his
CD4 count was 684 cells/ml and his viral load was over 1
million copies/ml. He was quickly enrolled in the QUEST
study, which offered AZT, 3TC, abacavir and amprenavir
for 25 months, with the addition of the Alvac
vaccination at months 19-25. At time of diagnosis he was
found to have no primary resistance mutations and to
have been infected with a subtype AE virus.
His viral load declined rapidly within six weeks of
initiating HAART to around 1000 copies/ml. Following a
six week treatment interruption due to hepatitis B,
treatment was re-started and his viral load declined to
below 50 copies/ml. In January 2001 HAART was stopped;
his viral load whilst on treatment had always been below
200 copies. By February his viral load had risen to
18,000 copies/ml and then to 80,000 copies/ml. Two weeks
later it had declined again to 21,000 copies/ml (first
rebound).
Two weeks later in April a rapid increase in viral load
occurred (second rebound) during which time his viral
load fluctuated between 200,000 and 400,000 copies/ml.
Sequencing at this point revealed a subtype B infection
and the man's symptoms were mild, he had transient
fatigue and fever and the patient declined the
re-introduction of HAART. Co-infection at the time of
acute infection, back in November 1998 and during the
following two years was excluded by using subtype
specific PCR tests on saved plasma samples.
The patient's history revealed several unprotected
sexual contacts in Brazil three weeks before the second
viral rebound. Serological data and quantification of
hepatitis C RNA also documented an acute Hepatitis C Virus infection
of genotype 3A.
HIV-1 superinfection has previously been induced in
chimpanzees. In this animal model the second infection
produces a slower immune deterioration and more
efficient control of viraemia in comparison to the
initial infection. Superinfection has been considered a
rare event and it was thought that it was prevented by
previous viral exposure, through a phenomenon called
superinfection immunity.
In the man, however, the biological course of HIV-1
infection was characterized by the persistence of high
viraemia and loss of 300 CD4 cells. This indicates that
subtype B produced a rapid disease progression. Natural
infection in humans, unlike chimps does not necessarily
induce crossclade protection.
This case study underlines the importance of the
maintenance of safer sexual practices among people
living with HIV.
A second case, presented at the same conference,
demonstrated that a superinfection may be acquired
during primary infection, but it is unclear if the
findings of this case study are applicable to patients
with long-established (chronic) HIV infection.
In 2002 researchers from the University of Geneva,
Switzerland, presented a case study of a 38-year-old gay
man who was infected with two different subtypes of HIV
on two different occasions more than two and a half
years apart (Jost 2002).
Dr Bruce Walker of Harvard Medical School reported a
further case at the 14th International AIDS Conference
in Barcelona in 2002. A man involved in a treatment
interruption study had achieved virological control
after three cycles of treatment and interruption. When
viral breakthrough appeared to occur, Dr Walker and his
team investigated the case in detail.
Dr Walker found that the man had been infected with a
new B clade virus following an unprotected sexual
encounter. The new virus was only 12% different to the
man´s original virus, nevertheless he was unable to
control the second infection. The existing HIV-specific
CD8 immune response was less able to recognise the new
virus, leading to uncontrolled viral replication.
These case studies suggest that superinfection with a
different version of HIV can occur. However, there is
not information about how frequently it occurs.
Two recent studies suggest that superinfection may not
be a common event. In the first study, 15 HIV-positive
couples had virus was sampled every six months for at
least two years. No evidence of superinfection was
discovered. In the second study, an analysis of protease
and reverse transciptase sequences from 3155 San
Francisco patients failed to show any evidence of
superinfection. In this study, researchers were looking
for close resemblences between the sequences (Chakraborty
2002; Shafer 2002).
Superinfection can be induced in the test tube in the
presence of 3TC, where drug resistant viruses are fitter
than wild type, thus out-competing them and preventing
re-infection with the wild-type virus as long as the
selective pressure of 3TC treatment is maintained (Chakraborty
2002).
The potential for superinfection has implications for
vaccine development.
Key
research
van der Vijver (2003) presented
data on 1,633 newly HIV-infected people recruited from
16 European countries and from Israel between 1996-2002
(CATCH study). Data gathered from France and the UK were
not included. 72% of the group were male, and 69% were
infected with HIV subtype B. Overall, primary resistance
mutations were detected in 9.6% of the cohort. By drug
class, mutations associated with resistance to NRTIs
were seen in 6.9%, to NNRTIs in 2.6%, and to PIs in
2.2%. Genotypic resistance to two or more classes was
noted in 1.7%. Primary resistance mutations were
detected in 157 CATCH participants. Interpretation of
these 157 genotypes forecast reduced 3TC susceptibility
in 17%, and in 40% for AZT and d4T. 26% were predicted
to harbour reduced NNRTI susceptibility, and between 10%
and 22% reduced susceptibility to PIs, depending on the
drug. Resistance mutations were more common in people
infected with subtype B than with a non B subtype (11.3%
versus 3.3%).
Chan (2003) has reported two
patients infected with drug-resistant virus in
Vancouver, Canada, did not experience a
"reversion" to wild-type virus. In contrast,
the individuals from whom HIV was contracted did revert
to wild-type HIV when treatment was stopped. In both of
the newly infected individuals, resistant-virus was
associated with a rapid decline in CD4 cell numbers and
a poor response to therapy.
Little (2002) reported on 377
people infected in 10 US cities between May 1995 and
June 2000. 3.4% of those infected during 1995-98 were
infected with highly resistant virus. During 1999-2000,
12.4% of newly infected individuals contracted a
drug-resistant strain. This was reflected in an increase
in resistance to all three main drug classes, and in an
increase from 1.1% to 6.2% in multi-drug resistant
virus. After initiation with antiretroviral therapy,
time to viral suppression was longer in people with
resistant virus, and time to treatment failure was
shorter.
Simon (2002) compared genotypic
and phenotypic resistance in 76 people with primary HIV
infection in New York between 1995-1998 and 78 infected
between 1999-2001. Protease inhibitor (PI)-associated
mutations rose from 13.2% to 19.7% over time. Prevalence
of phenotpyic resistance to nucleoside analogues (NRTIs)
fell from 8.3% to 2.7%, non-nukes (NNRTIs) rose from 5%
to 8.1%, and PIs from 1.7% to 5.4%. The decline in NRTI
resistance was due to a decrease in the number of people
with 3TC resistance. However, the number of people with
the 215 mutation associated with resistance to multiple
NRTIs rose to 5%.
Grant (2002) studied 225
consecutive cases of primary HIV infection at a San
Francisco Hospital between June 1996-June 2001. The
prevalence of drug-resistant mutations in 1996-97 and
2000-01 was compared. Genotypic resistance to NNRTIs
rose from 0% to 13.2%; PI mutations from 2.5% to 7.7%.
Genotypic resistance to 2 classes rose from 2.5% to
6.2%. The prevalence of phenotypic resistance rose from
2.6% to 6.2% for PIs, from 0% to 9.9% for NNRTIs, and
fell from 21% to 6.2% for NRTIs.
The UK Collaborative Group
investigated the prevalence of key resistance mutations
among 69 newly infected individuals June 1994-August
2000, prior to antiretroviral therapy. Overall, 14%
showed drug resistance. 3% were infected with a virus
resistant to all three clases of drugs. 2/44 people
tested prior to 2000 were infected with a drug
resistance virus compared with 7/26 tested in 2000. The
risk of being infected with a resistant virus increased
over time. The estimated prevalence of HIV drug
resistance among newly infected individuals in the UK in
2000 was 27%.
Yerly (2001) analysed HIV from 82
consecutive cases of primary HIV infection for protease
inhibitor and nucleoside analogue resistant mutations
between January 1996-July 1999. In total, 9 of 82 (11%)
individuals were infected with HIV that was resistant to
one or more anti-HIV drugs. Seven people (9%) had
AZT-associated mutations (M41L. D67N, K70R, T215Y/F).
Two had the M184V mutation associated with 3TC
resistance plus mutations associated with nevirapine
resistance (Y181C and G190A). Three (4%) had mutations
associated with primary PI resistance (V82A, L90M) with
13 people having between 2-4 secondary PI-associated
mutations. Two individuals were infected with HIV that
contained mutations causing PI and NRTI resistance.
Descamps (2001) reported
genotypic analysis of 404 newly diagnosed HIV patients
in France in 1998. 3.3% had resistance to NRTIs, 0.8% to
the NNRTIs and 1.9% to the PIs. Harzic (2002)
subsequently updated French resistance data in newly
infected people.
Becker (2002) conducted a study
of 281 people commencing treatment at 100 sites in the
US. 8.9% had evidence of resistance (5.3% NNRTI, 3.5%
NRTI, 0.7% PI, 0.7% at least two drug classes).
Verbiest (2001) analysed blood
samples from 230 HIV-infected, untreated individuals.
Genotypic/phenotypic testing found 2%/1.6% had high
level NRTI resistance, and 5%/4.7% had moderate NRTI
resistance. For NNRTIs, 6%/42% had moderate resistance
and 7%/23% had high level resistance. For PIs, 2%/1.6%
had high level resistance and 38%/3% had moderate
resistance. The overall prevalence of resistance was
about 10%.
Brenner (2000) reported
prevalence of drug resistance among newly infected
people in Quebec between 1997-1999. 15% had PI
resistance, 6% had NRTI resistance, 5% had NNRTI
resistance and 10% had multidrug resistant virus.
Salomon (2000) further reported no significant different
in transmission of resistant virus based on sexual or
injecting exposure.
Wegner (2000) analysed HIV from
114 treatment-naive people infected within the last 3
years for phenotypic and genotypic resistance. 15% of 95
subjects had genotypic resistance and 26% of 91 had
phenotypic resistance to the NNRTIs. Genotypic and
phenotypic resistance were found in 4% and 8% of people
for NRTIs, and in 10% and 1% for PIs.
Miller (1999) reported baseline
mutations in 46 people with primary infection from the
international QUEST study reported. Two had AZT
resistance mutations, two had 3TC mutations, one had the
215 mutation, and two had the NNRTI mutation V106I. No
primary protease inhibitor mutations were detected, but
11 people had minor protease inhibitor mutations.
Weinstock (2000) studied
resistance mutations among untreated, newly infected
individuals between 1993-1998. 6% had AZT-associated
mutations. 1% had PI resistance and 2% had NNRTI
resistance. Overall, 5% of participants had been
infected with a mutant virus but only 1% had highly
resisant virus.
Loveday (1999) compared
resistance mutations in 54 untreated individuals with
nine archived samples from 1986. 27/54 had at least one
resistance mutation: 6 with RT mutations, 21 with
protease mutations, and 4 with both. Mutations were
secondary rather than primary resistance mutations. The
rate of naturally occurring polymorphisms had not
changed between 1986 and 1998.
Tamalet (2000) studied 48 newly
infected individuals and found that 2% had major
mutations associated with PI resistance although 73% had
other mutations in the protease gene. 17% had mutations
associated with NRTI resistance. However, the presence
of mutations did not predict treatment failure after 18
months follow-up.
Boden (1999) studied 80 newly
infected individuals, mainly gay men, infected between
1995-1999. Resistance mutations were common: 7.5% AZT,
5% 3TC, 7.5% NNRTIs, 2.5% PIs, multidrug resistant virus
3.8%. Resistance testing showed about 1 in 5 newly
infected individuals in this study had some drug
resistance.
Machado identified 19 of 35
HIV-infected blood donations in the US in 1995/96 had
HIV with protease inhibitor-associated mutations. The
blood donors were all recently infected, suggesting
recent ongoing transmission of PI-resistant virus, or
else a high frequency of virus with natural mutations
(polymorphisms) which might make them less sensitive to
protease inhibitors.
Van Vaerenbergh (2001) reported a
Belgian study of HIV-infected people attending a
hospital for the first time in 1995, 1997 and 1998
showed no significant increase in the prevalence of
resistance mutations. Between 10-20% had NRTI or NNRTI
resistance and 5-8% had PI resistance. Overall, the
proportion of people with any genotypic resistance rose
from 27% to 31%.
Duwe (2001) reported a review of
54 patients from Berlin which found that 13% of recent
seroconverters identified between 1996 and 1999 had
reduced sensitivity (phenotypic resistance) to at least
one drug, in most cases to the nucleoside analogues AZT
or 3TC. Only one PI-resistant strain was identified, and
no multi-drug resistant isolates were identified.
References
Alexander CS et al. Prevalence
of primary HIV drug resistance among seroconverters
during an explosive outbreak of HIV infection among
injecting drug users. AIDS 13(8):981-985, 1999.
Becker M et al. HIV-1 genotypic
resistance in treatment-naive subjects enrolled in an
observational trial (GAIN). Antiviral Therapy 7: S134,
2002.
Bennett D et al. Prevalence of
mutations associated with antiretroviral drug resistance
among recently diagnosed persons with HIV, 1998-2000.
Ninth Conference on Retroviruses and Opportunistic
Infections, Seattle, abstract 372, 2002.
Bielawski KP et al. Occurrence
of HIV-1 drug-resistant mutations in Poland among
patients selected for HAART. First European HIV
Resistance Workshop, Luxembourg, abstract 66, 2003.
Boden D et al. Resistance to
human immunodeficiency virus type 1 protease inhibitors.
Antimicrobial Agents and Chemotherapy, 1998.
Boden D et al. HIV-1 drug
resistance in newly infected individuals. Journal of the
American Medical Association 282:1135-1141, 1999.
Brenner B et al. Resistance to
antiretroviral drugs in patients with primary HIV-1
infection. Investigators of the Quebec Primary Infection
Study. International Journal of Antimicrobial Agents
16(4):429-434, 2000.
Brenner BG et al. Persistence
and fitness of multidrug resistant human
immunodeficiency virus type 1 acquired in primary
infection. Journal of Virology 76 (4): 1753-1761, 2002.
Brindeiro RM et al. Brazilian
Network for HIV Drug Resistance Surveillance (HIV-BResNet):
a survey of chronically infected individuals. AIDS
17(7):1063-1069, 2003.
Briones C et al. Primary
genotypic and phenotypic HIV-1 drug resistance in recent
seroconverters in Madrid. Journal of Acquired Immune
Deficiency Syndromes 26(2):145-150, 2001.
Chaix ML et al. Antiretroviral
resistance, molecular epidemiology and response to
initial therapy among patients with HIV-1 primary
infection in 1999-2000 in France. Antiviral Therapy 7:
S138, 2002.
Chakraborty B et al. Evaluating
HIV-1 superinfection in cell culture, the SCID-hu Thy/Liv
model and HIV-infected individuals with high risk of
re-exposure to the virus. Antiviral Therapy 7: S47,
2002.
Chan KCW et al. Prolonged
retention of drug resistance mutations and rapid disease
progression in the absence of therapy after primary HIV
infection. AIDS 17(8): 1256-1258, 2003.
Cohen and Fauci. Transmission
of multidrug-resistant human immunodeficiency virus --
the wake-up call. New England Journal of Medicine 339
(5): 341-343, 1998.
Daar ES et al. Protease
inhibitor(PI)- and non-(PI)-containing antiretroviral
therapy (ART) compared to no treatment in primary HIV
infection (PHI). Eighth Conference on Retroviruses and
Opportunistic Infections, Chicago, abstract 402, 2001.
Dann LC et al. Frequency of
mutations associated with antiretroviral drug resistance
in patients undergoing acute HIV-1 infection (PHI).
Fifth International Congress on Drug Therapy in HIV
Infection, Glasgow, abstract P363, AIDS 14(supp 4):S122,
2000.
Dean GL et al. Incidence of
transmitted antiretroviral drug resistant HIV may be
rising in the UK. Fifth International Congress on Drug
Therapy in HIV Infection, Glasgow, abstract P364, AIDS
14(supp 4):S122, 2000.
de Mendoza C et al. Decline in
the rate of genotypic resistance to antiretroviral drugs
in recent HIV seroconverters in Madrid. AIDS
16(13):1830-1832, 2002.
DePasquale MP et al. Primary
HIV infection: in vivo fitness of pre-therapy resistant
mutants and potential for secondary spread of HIV from
semen. Antiviral Therapy 4(supplement 1):89, 1999.
Descamps D et al. Prevalence of
resistance mutations in antiretroviral-naive chronically
HIV-infected patients in 1998: a French nationwide
study. AIDS 15(14):1777-1782, 2001.
Duwe S et al. Frequency of
genotypic and phenotypic drug-resistant HIV-1 among
therapy-naive patients of the German Seroconverter
Study. Journal of Acquired Immune Deficiency Syndromes
26(3):266-273, 2001.
Erice A et al. Analysis of
HIV-1 reverse transcriptase and protease sequences in
paired plasma and lymphoid tissue specimens from HIV-1
infected individuals. AIDS 15(7):831-836, 2001.
Eron JJ et al. Resistance of
HIV-1 to antiretroviral agents in blood and seminal
plasma: implications for transmission. AIDS
12(15):F181-189, 1998.
Fang et al. Complete HIV pol
sequence in plasma and genital tract of women: genital
reservoir and differential drug resistance. 38th
Interscience Conference on Antimicrobial Agents and
Chemotherapy, San Diego, abstract I-122, 1998.
Grant RM et al. Time trends in
primary HIV-1 drug resistance among recently infected
persons. Journal of the American Medical Association
188(2):181-188, 2002.
Grant RM et al. Transmission of
drug resistant HIV-1 exhibiting lower replication
capacity is associated with higher CD4 cell counts.
Antiviral Therapy 7: S41, 2002.
Harzic M et al. Genotypic drug
resistance during HIV-1 primary infection in France
(1996-1999): frequency and response to treatment. AIDS
16(5):793-796, 2002.
Hazelwood JD et al. Detection
of RT and protease resistance in genital tract and
plasma viruses from an HIV-infected woman receiving
highly active antiretroviral triple therapy: a case
report. Antiviral Therapy 4(supplement 1):96, 1999.
Hecht FM et al. Sexual
transmission of an HIV-1 variant resistant to multiple
reverse-transcriptase and protease inhibitors. New
England Journal of Medicine 339 (5): 307-311, 1998.
Hecht FM et al. Transmission of
specific antiviral resistance mutations within partner
pairs. Eighth Annual Conference on Retroviruses and
Opportunistic Infections, abstract 87, 2001.
Holodniy M et al. Discordance
between blood plasma and seminal fluid HIV RNA codon 215
genotypes during acute HIV transmission. Second National
Conference on Human Retroviruses and Related Infections,
Washington, abstract 238, 1995.
Iversen AKN et al.
Multidrug-resistant human immunodeficiency virus type 1
strains resulting from combination antiretroviral
therapy. Journal of Virology 70(2):1086-1090, 1996.
Jost S et al. A patient with
HIV-1 superinfection. New England Journal of Medicine
347(10):731-736, 2002.
Kucherer C et al. Transmission
of drug-resistant HIV: an update of the German
seroconverter study. First European HIV Resistance
Workshop, Luxembourg, abstract 55, 2003.
Leigh Brown AJ et al.
Transmission fitness of drug-resistant human
immunodeficiency virus and the prevalence of resistance
in the antiretroviral-treated population. Journal of
Infectious Diseases 187(4):683-686, 2003.
Little S et al. Reduced
antiretroviral drug susceptibility among patients with
primary HIV infection. Journal of the American Medical
Assocation 282:1142-1149, 1999.
Little SJ. Is transmitted drug
resistance in HIV on the rise? (editorial) British
Medical Journal 322(7294):1074, 2001.
Little S et al.
Antiretroviral-drug resistance among patients recently
infected with HIV. New England Journal of Medicine
347(6):385-394, 2002.
Loveday C et al. High
prevalence of multiple drug resistance mutations in a UK
HIV/AIDS patient population. AIDS 13(5):627-628, 1999.
Machado D et al. env and pol
polymorphism in US blood donors with recently acquired
HIV infection. Sixth Conference on Retroviruses and
Opportunistic Infections, Chicago, abstract 216, 1999.
Miller V et al. Prevalence of
baseline drug resistance mutations in primary HIV
infection patients from the QUEST study. Antiviral
Therapy 4(supplement 1):98 1999.
Paxinos EE et al. Natural
variation in susceptibility to non-nucleoside reverse
transcriptase inhibitors predates drug availability.
Antiviral Therapy 5 (3), abstract 156, 2000.
Periera A et al. Nucleoside
analogues achieve high concentrations in seminal plasma:
relationship between drug concentration and virus
burden. Journal of Infectious Diseases 180(6):2039-2043,
1999.
Pillay D et al. Detection of
drug resistance associated mutations in HIV primary
infection within the UK. AIDS 14(7):906-908, 2000.
Pillay D et al. The impact of
transmitted resistance on time to CD4< 350 cells/ml.
Antiviral Therapy 7: S147, 2002.
Puig T et al. Prevalence of
genotypic resistance to nucleoside analogues and
protease inhibitors in Spain. The ERASE-2 Study Group.
AIDS 14(6):727-732, 2000.
Quigg M et al. Mutations
associated with zidovudine resistance in HIV-1 among
recent seroconvertors. AIDS 11(6):835-836, 1997.
Routy JP et al. Link between
the declines of drug-resistance prevalence in newly
infected individuals and of the proportion of patients
receiving treatment in Montreal. Antiviral Therapy 7:
S147, 2002.
Salomon H et al. Prevalence of
HIV-1 resistant to antiretroviral drugs in 81
individuals newly infected by sexual contact or
injecting drug use. Investigators of the Quebec Primary
Infection Study. AIDS 14(2):F17-23, 2000.
Shafer RW et al. Failure to
detect HIV-1 re-infection based on serial protease and
reverse transcriptase sequences during 1239 patient
years observation. Antiviral Therapy 7: S149, 2002.
Simon V et al. Evolving
patterns of HIV-1 resistance to antiretroviral agents in
newly infected individuals. AIDS 16(11):1511-1519, 2002.
Sonnenborg A et al. Clinical
issues and assays. Fourth International Congress on Drug
Therapy in HIV Infection, Glasgow, abstract PL 3.3,
1998.
Tamalet C et al. Prevalence of
drug resistant mutants and virological response to
combination therapy in patients with primary HIV-1
infection. Journal of Medical Virology 61(2):181-186,
2000.
Taylor S et al. Poor
penetration of the male genital tract by HIV-1 protease
inhibitors. AIDS 13(7):859-860, 1999.
UK Collaborative Group on
Monitoring the Transmission of HIV Drug Resistance.
Analysis of prevalence of HIV-1 drug resistance in
primary infections in the United Kingdom. British
Medical Journal 322(7294):1087-1088, 2001.
van der Vijver DAMC et al.
Analysis of more than 1600 newly diagnosed patients with
HIV from 17 European countries shows that 10% of the
patients carry primary drug resistance: The CATCH study.
Second International AIDS Society Conference, Paris,
late breaker 1, 2003.
van Vaerenbergh K et al.
Prevalence and characteristics of
multinucleoside-resistant human immunodeficiency virus
type 1 among European patients receiving combinations of
nucleoside analogues. Antimicrobial Agents and
Chemotherapy 44(8):2109-2117, 2000.
Verbiest W et al. Prevalence of
HIV-1 drug resistance in antiretroviral-naive patients:
a prospective study. AIDS 15(5):647-650, 2001.
Wegner S et al. Prevalence of
genotypic and phenotypic resistance to anti-retroviral
drugs in a cohort of therapy-naive HIV-1 infected US
military personnel. AIDS 14(8):1009-1015, 2000.
Weinstock H et al. Prevalence
of mutations associated with reduced antiretroviral drug
susceptibility among human immunodeficiency virus type 1
seroconverters in the United States, 1993-1998. Journal
of Infectious Diseases 182(1):330-333, 2000.
Wensing AMJ et al. Combined
analysis of resistance transmission over time of
chronically and acutely infected HIV patients in Europe.
First European HIV Resistance Workshop, Luxembourg,
abstract 54, 2003.
Williams I et al.
Antiretroviral drug resistant genotypic mutations in
HIV-infected persons at first diagnosis (1988-97).
Second International Workshop on HIV Drug Resistance and
Treatment Strategies, Lake Maggiore, abstract 116, 1998.
Yerly S et al. Transmission of
antiretroviral-drug-resistance HIV-1 variants. Lancet
354(9180):729-733, 1999.
Yerly S et al. Peak in the
transmission of drug-resistant variants in 1997 is
followed by a reflux in Switzerland. Fourth
International Workshop on HIV Drug Resistance and
Treatment Strategies, abstract 185, 2000.
Yerly S et al. HIV drug
resistance and molecular epidemiology in patients with
primary HIV infection. Eighth Conference on Retroviruses
and Opportunistic Infections, Chicago, abstract 754,
2001.
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