Click a topic below for an index of articles:

 

New-Material

News Letter

Home

Donate

Alternative-Treatments

Financial or Socio-Economic Issues

Forum

Health Insurance

Hepatitis

HIV/AIDS

Institutional Issues

International Reports

Legal Concerns

Math Models or Methods to Predict Trends

Medical Issues

Our Sponsors

Occupational Concerns

Our Board

Projects

Religion and infectious diseases

State Governments

Stigma or Discrimination Issues

If you would like to submit an article to this website, email us at info@heart-intl.net for a review of this paper
info@heart-intl.net

 

any wordsall words
Results per page:

“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”


Transmission of drug-resistant HIV

http://www.aidsmap.com/treatments/ixdata/english/27a9ff69-3c3d-4f68-aca1-cc7aa10a260e.htm

 

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However, this work has been superseded.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.