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?

Wide variations in the prevalence of drug-resistant HIV in newly infected and treatment-naive individuals have been reported, together with differences in the rates of change in prevalence over time.

Across Europe, an average of about 10% of newly acquired HIV is drug-resistant, according to two studies. A large study known as CATCH assessed resistance in over 1630 newly infected people in Europe between 1996 and 2002. Overall, primary resistance mutations were detected in 10% of the group. By drug class, mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) were seen in 7% of participants, to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 3%, and to protease inhibitors (PIs) in 2% (van der Vijver 2003). A second pan-European analysis of 2208 seroconverters presented in 2003 found evidence of drug resistance in 11% of patients (Wensing 2005). Similar rates of resistance were found in the SPREAD study of 1083 seroconverters from 17 European countries, with only 1% of the study groupr demonstrating dual-class resistance (Wensing 2006).

In the United Kingdom, 27% of people who contracted HIV in 2000 were infected with drug-resistant virus. From 1994 to 2000, 14% of seroconverters had resistant virus (UK Collaborative Group 2001). In 2002, 27% of gay men identified as recent seroconverters in England, Wales and Northern Ireland had resistance to at least one drug, compared to 20% in 2002 (Rinck 2004).

One of the most recent prevalence studies of transmission of drug-resistant HIV was conducted by French researchers who used data from two cohorts: 303 patients with acute HIV infection (the Primo study) and 363 treatment-naive patients infected with HIV for a median of six months (the Odyssee study). Using the International AIDS Society-USA Resistance Testing Panel list of mutations, 14% of patients in the Primo study had resistance mutations. Ten per cent had resistance to NRTIs, 3% to NNRTIs and 4% to PIs. In the Odyssee cohort the overall prevalence was 6% (4% to NRTIs, 1% to NNRTIs and 1% to PIs). When French guidelines to assess resistance were used prevalence was estimated at 12% and 2%, respectively (Descamps 2005).

Estimates of what proportion of people are contracting drug-resistant HIV in the United States also vary. A recent survey of treatment-naive people across 40 United States cities showed that 8% had drug-resistant virus (Ross 2004). In some studies, nearly a quarter of newly infected people have acquired drug-resistant virus (Little 2002; Simon 2002). Studies of people starting treatment for the first-time in the US indicate about 9% have some resistance to treatments (Becker 2002; Weinstock 2004).

Is the proportion of seroconverters with drug-resistant forms of HIV increasing?

There is conflicting evidence on this question.

Some studies suggest an upward trend the proportion of people becoming infected with a drug-resistant strain of HIV. In the United Kingdom the prevalence of drug-resistant HIV in newly infected gay men rose from 20% in 2001 to 27% in 2002, according to data from the Health Protection Agency (Rinck 2004). The UK Collaborative Group on Monitoring Transmission of HIV Drug Resistance has also reported a significant increase in the proportion of newly infected people who have contracted a resistant strain of HIV in 2000 to 2001. A large study of 377 seroconverters from ten United States cities has reported that more people are contracting drug-resistant HIV. Between 1995 and 1998, only 3% of seroconverters had resistant virus compared to 12% in 1999 and 2000 (Little 2002).

However, other evidence 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 viral load 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 15% in 1997 and 9% in 1996.

Similarly, a study of 209 seroconverters 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). French surveillance of seroconverters failed to detect any increase in drug resistance in the period 1999 to 2000 compared with 1996 to 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).

A study carried out between June 2000 and March 2002 found no significant increase in transmitted drug resistance when this period was compared with 1995 to 1998 and 1998 to 2000. Indeed, NRTI and PI resistance in seroconverters declined significantly when 2000 to 2002 was compared with 1998 to 2000, with much of the resistance detected in the 2000 to 2002 period attributable to NNRTI resistance. Multidrug resistance declined significantly, from 7 to 1% (Little 2002b).

Other studies suggest a more complex picture, with the prevalence of resistance in people with newly acquired HIV varying by drug class. A San Francisco study has also an upward trend in the proportion of people becoming infected with a drug-resistant strain of HIV. By 2000 to 2001, 13% of seroconverters had a virus resistant to NNRTIs and 8% were resistant to 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% between 1995 and 1998 to 3% in 1999 and 2001), attributing this shift to a fall in the number of people with 3TC (lamivudine, Epivir) resistance. However, this decline was offset by an increasing number of people with PI and NNRTI resistance. By 1999 to 2001, nearly 20% were infected with virus which showed resistance mutations to NNRTIs and PIs. Eight per cent had phenotypic resistance to NNRTIs and 5% had resistance to PIs (Simon 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, a drop in the average viral load of chronically infected people and the availability of resistance testing (Routy 2002, 2004).

Transmission of drug-resistant HIV in resource-limited settings

Little surveillance evidence exists to date on the prevalence of drug-resistant HIV in resource-limited settings. However, the World Health Organization and the International AIDS Society have established a joint surveillance project to track prevalence of genotypic resistance in treatment-naﶥ people after the introduction of antiretroviral therapy in specific settings.

So far, the only such country in which resistance has been systematically studied in treatment-naive people is Brazil, where a national survey found that around 2% showed genotypic resistance to each of the three drug classes, and 8% showed resistance to at least one drug. A smaller pilot survey among 71 treatment-naive patients in Rio de Janeiro found only one case of drug resistance, associated with 3TC (Dias Tavares 2003).

Transmission of nucleoside reverse transcriptase inhibitor-resistant virus

Initial reports about the transmission of drug-resistant HIV concerned resistance to NRTIs. Swiss researchers tested for AZT (zidovudine, Retrovir)-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. They calculated that between 1991 and 1994, around 10% of new infections involved AZT-resistant virus. During the era of monotherapy and dual therapy with NRTIs, the prevalence of NRTI resistance in newly infected people ranged from 10 to 42%.

Since the early days of AZT monotherapy, virus which is resistant to several NRTIs has been transmitted. Figures from the United States showed the proportion of newly infected people who acquired a NRTI-resistant virus rose from 3% in the mid-1990s to 8% in 1999 and 2000 (Little 2002).

As described above, several recent studies have suggested that a smaller proportion of newly infected people have NRTI resistance, possibly reflecting improvements in antiretroviral therapy. However, in chronically infected, untreated people, NRTI resistance remains the most prevalent form of resistance (Novak 2005).

Transmission of protease inhibitor-resistant virus

United States researchers documented a case of transmission of virus with reduced susceptibility to AZT, 3TC, ddC (zalcitabine, Hivid) and all PIs in 1998 (Hecht 1998). 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 unprotected anal intercourse (Boden 1999). There has also been a case report of a baby who contracted a multi-drug resistant strain of HIV from its mother.

In 1998 Swiss researchers reported that 5% of those identified as seroconverters between 1996 and 1998 period had acquired HIV with PI mutations. There has also been one report of the transmission of a multi-NRTI, multi-PI resistant virus in the United States.

Data from the United States showed that the proportion of people contracting PI-resistant virus rose from less than 1% between 1996 and 1998 to 8% between 1999 and 2000 (Little 2002). As with NRTIs, transmission of PI-resistant HIV may be stabilising or declining as the potency of treatments improves.

Transmission of non-nucleoside reverse transcriptase inhibitor-resistant virus

A clear understanding of transmission of NNRTI-resistant virus was complicated in the 1990s when natural variations or polymorphisms were mistakenly identified as drug resistant mutations. These natural mutations were subsequently recognised to have little impact of antiviral efficacy (Boden 1999; Loveday 1999).

There is a trend indicating that transmission of NNRTI-resistant virus is becoming more common in the United States. Rates of NNRTI-resistant virus were about 1% between 1996 and 1998 and rose to 7% between 1999 and 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 to 2001 was 27%, similar to the 25% prevalence found in 1996 and 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% 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 1998; Fang 1998). 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 PI 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 1999), PIs do not always appear to reach adequate concentrations in semen (Taylor 1999).

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 transmissibility of drug-resistant viruses by blood or by sexual intercourse (Salomon 2000).

Resistance and reduced infectiousness

Although between 3 and 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 eleven 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 2001).

Persistence of drug-resistant virus

A consensus appears to have emerged among HIV experts, based on a significant body of research, that resistance mutations present at the time of infection may remain present over many years in the absence of treatment. This is different to patients who develop drug resistance mutations during treatment. If these patients stop taking antiretroviral therapy, there is usually a reversion to the fittest strain of HIV in their body, the wild-type strain. However, in patients who were infected with a resistant strain, there is no wild-type strain archived in the body to become dominant, and random mutation of the virus to become wild-type is a very rare event.

Most recently, results of a large American study suggest resistance mutations persist over eight years of infection. The investigators from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) study team analysed the genetic make-up of HIV from 491 patients randomly selected from the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial. None of the patients had taken any antiretroviral therapy. Their mean CD4 cell count was 269 cells/mm³ and 31% had a previous AIDS diagnosis, corresponding to an expected infection duration of seven to eight years.

Defining resistance according to the International AIDS Society 2003 guidelines, plus additional mutations at positions 215 and 69 of the reverse transcriptase enzyme, the researchers saw that 57 patients (12%) had at least one resistance mutation, and they estimated that 11% of the cohort had drug-resistant virus. The investigators estimated the prevalence of NRTI resistance mutations to be 8%. In contrast, it was 3% for NNRTIs and 1% for PIs, although only primary protease mutations were included in the analysis (Novak 2005).

A British study of 14 people with primary HIV infection with a drug-resistant strain found that the vast majority of drug-resistant viruses persisted over two to 36 months follow-up (Pao 2005). Multidrug resistance in two of these cases was found to be stable for over 18 months. Key NRTI and PI mutations remained static but in two cases NNRTI mutations disappeared in the long term.

There is evidence that multidrug-resistant virus may be quite resilient when acquired through transmission. One study of six patients with multidrug resistant virus who were followed for a period of two to seven years from infection showed that the pattern of resistance mutations carried by their HIV scarcely changed. The only exception was that the M184V mutation reverted to wild type in two patients, and a viral load increase did occur associated with that reversion (Brenner 2000, 2002, 2004). Other studies have also confirmed the persistence of resistant virus, including multidrug-resistant virus, over time periods of up to seven years (Barbour 2004; Delaugerre 2003; Ravaux 2003).

Other cases of disappearance of the M184V mutation associated with 3TC resistance have been reported over six to twelve months after primary infection (Little 2004).

Despite the persistence of transmitted resistant HIV, use of genotypic testing can lead to choice of appropriate first-line treatment regimens, as recommended in current guidelines from the United Kingdom and the United States. An analysis of the international CASCADE collaboration showed that this selection of drugs results in similar outcomes in patients with and without primary resistance (Pillay 2004). However, it is possible that second- and third-line treatment options may be limited in these patients due to an exhaustion of effective drugs.

Implications for prognosis

At the Seventh International Congress on Drug Therapy in HIV Infection in 2004, Dr Mark Wainberg of McGill University AIDS Centre in Montreal, Canada, argued that the clinical consequences of infection with multidrug resistant virus were unpredictable, varying from repeated treatment failure to long-term non-progression. Low replicative capacity of multidrug resistant virus may correlate with low viral load and delayed progress, but this theory is yet to be proven.

Recent publicity given to the case of a man in New York who experienced rapid disease progression after infection with multidrug-resistant HIV. The man was diagnosed with HIV in December 2004, having previously received a negative test result in May 2003. However, he subsequently had unprotected anal sex with multiple male partners, often after taking the recreational drug methamphetamine. The man was infected with 3-DCR HIV, a strain of HIV resistant to three of the four classes of antiretroviral drugs.

However, experts discussing the case at the Twelfth Conference on Retroviruses and Opportunistic Infections in Boston in early 2005 said that this isolated case report does not indicate that the HIV strain found in this patient is aggressive, since disease progression is determined by the complex interaction between the virus and the hosts genetic make-up (Markowitz 2005a,b). In addition, the probable source patient for this man's HIV strain who has recently been identified, did not experience rapid HIV disease progression despite their viruses being over 99% identical (Blick 2005). This suggests that the host's immune response may be more important in determining the speed of progression than the virus's virulence.

The New York man had extensive genotypic resistance but phenotypic analysis of the virus revealed that it is fully susceptible to two antiretrovirals: efavirenz (Sustiva) and to the fusion inhibitor T-20 (enfuvirtide, Fuzeon), and he is currently on therapy.

In addition to the limited treatment options available to people infected with this strain of virus, two other factors suggest rapid disease progression is likely. First, despite the number of resistance mutations, this virus is able to replicate effectively, with a replication capacity by the PhenoSense assay 1.38 times greater than wild-type virus. Second, the virus is dual tropic (that is, it uses both co-receptors) and it produces clumping of infected cells. This is associated with the CXCR4 co-receptor and advanced disease. Of note, the presumed source patient's virus was CCR5-tropic and less virulent, with a replicative capacity of less than half that of wild-type virus.

While coverage of high-profile case studies such as this might suggest that becoming infected with a multidrug-resistant virus spells doom, several studies suggest that infection with a resistant strain of HIV does not appear to influence the rate of disease progression nor does it mean an absence of treatment options.

Although people infected with drug-resistant virus may experience a slightly greater CD4 cell count decline in the first year after infection, a comparison with people infected with wild-type virus showed similar rates of CD4 T-cell loss thereafter in the absence of treatment (Bhaskaran 2004).

It is unclear whether unfit virus with little capacity to replicate will mean slower progression. A survey of 101 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). Similar conclusions were reached in a three year follow-up of 46 Spanish seroconverters with available baseline genotypes (de Mendoza 2003). However, 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 after controlling for duration of infection (Grant 2002).

Of course, acquiring drug-resistant HIV is assumed to reduce treatment options but with resistance testing active regimens can be selected for many people in this situation. Furthermore, there is evidence that baseline resistance may also not affect the short-term efficacy of first-line antiretroviral therapy, according to data from the CASCADE study. However, experts suspect that second- and third-line therapy may be compromised by the acquisition of a drug-resistant form of HIV (Pillay 2004). Development of resistance to NRTIs and NNRTIs has been linked a greater risk of death in a large Canadian cohort followed between 1996 and 2003 (Hogg 2005).

Superinfection[ix]

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, particularly in people who have been HIV-positive for a less than two to three years.

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 viral load 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 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).

A further case was reported 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, the investigators investigated the case in detail, finding 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 (Walker 2002).

Similar cases have been reported in the United Kingdom and the United States, the latter showing a loss of response to antiretroviral therapy after superinfection (Booth 2006; Smith 2005).

Superinfection with wild type virus can also occur in the presence of drug-resistant virus (Koelsch 2003). In the reported case, superinfection with wild type virus was associated with a rapid decline in CD4 cell count from almost 800 cells/mm³ to a low point of 283 cells/mm³ at eleven months.

These case studies suggest that superinfection with a different version of HIV can occur. But how frequently does it occur?

Superinfection may not be a common event among people taking antiretroviral therapy, according to two recent studies. In the first study, 15 HIV-positive couples had virus 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 transcriptase sequences from 3155 San Francisco patients, most of whom were taking anti-HIV therapy, failed to show any evidence of superinfection. In this study, researchers were looking for close resemblances between the sequences (Chakraborty 2002; Shafer 2002).

However, a study of 78 recently infected individuals in San Francisco and Los Angeles has reported an annual rate of superinfection of 5% among people not taking antiretroviral therapy. Retrospective molecular analysis of blood samples collected between December 1997 and June 2003 discovered three cases of superinfection. Superinfection occurred between five and 13 months after the estimated date of initial infection (Smith 2004).

Even if the risk of superinfection is low for those on antiretroviral therapy, the rapid disease progression that can occur with superinfection might not be considered a risk worth taking. In the Californian study, each superinfecting HIV strain was associated with a change in susceptibility to antiretrovirals, even though none of the men were on therapy. Two were initially infected with drug-resistant HIV and then became superinfected with a wild-type strain, while the other was initially infected with a wild-type strain and then was superinfected with a drug-resistant strain. Within six months of acquiring the superinfecting strain, their viral loads increased significantly by an average of 1.6 log₁₀ and their CD4 cell counts decreased by an average of 132 cells/mm³. In another instance, superinfection led to the rapid onset of AIDS (within three-and-a-half years) and death (within six years) despite an initial good immune response to the first infection in a member of the MACS cohort (Gottlieb 2004).

A recent report suggest that superinfection may be more common during the early stage of HIV disease when the immune response to the virus is not well developed (Grant 2005).

Superinfections with a different subtype leading to recombinant viruses have been documented (Fang 2003), as have superinfections that lead to the existence of two circulating subtypes in an individual (Yerly 2003).

Key research on the transmission of resistant HIV

Little (2004) reported that an analysis of 12 people in Southern California has shown that specific drug resistance mutations may persist for at least one year after the estimated date of infection (Little 1999; 2004). Six patients with the K103N mutation associated with NNRTI resistance were shown to have this mutation more than one year after infection. Ten had acquired virus with NNRTI resistance, five had PI-resistant virus and five had nucleoside analogue (NRTI) resistant virus (two had virus resistant to agents in all three drug classes, and three had virus resistant to at least one drug in two drug classes). Only one individual with NNRTI-resistant virus experienced any increase in drug susceptibility during a median follow-up period of 310 days, and the mean time to the emergence of any variants without the acquired NNRTI mutation was 375 days. No PI mutations disappeared during the follow-up period. Virus with NRTI mutations began to disappear after an average follow-up of one year. The M184V mutation associated with 3TC treatment was identified in two patients, and reverted to wild type after 181 days and 327 days, respectively. Only one patient totally reverted to wild type virus, after follow-up of 2.8 years. In this sample, replication capacity was high despite mutations.

Pao (2004) reported that mutations associated with AZT and NNRTI resistance persisted for up to 33 months in individuals identified through a UK study of newly infected individuals. 14 patients with drug resistance were identified in this study. M41L, T69N, K103N, and T215 mutations showed little change and multidrug resistant virus demonstrated little reversion to wild-type virus. Y181C and K219Q associated with NNRTI resistance disappeared within 25 and 9 months, respectively in 2 people who had persistent PI mutations. Multidrug resistance was stable for up to 18 months in two individuals. .

Pillay presented analysis of first-line therapy in 20 people who had acquired drug-resistant virus and compared them to 132 patients without evidence of resistance (CASCADE study). There was no significant difference in the time taken to achieve a viral load below 500 copies/ml between individuals who were not fully sensitive to all agents in their first regimen and those who were judged fully sensitive by genotypic resistance test. They also found no evidence that transmitted resistance to a particular class of drug conferred a disadvantage, but they did suggest that transmitted resistance could affect response to second- and third-line regimens, since it may narrow the range of available drugs that could be used after the failure of the first regimen.

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 multidrug 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.

Wensing (2003) reported preliminary data from the SPREAD study involving five European countries. 9% of 348 recently infected people in 2002-03 had a virus which contained primary mutations.

Duwe (2001) found that 13% of 54 seroconverters in Berlin between 1996-1999 were infected with drug-resistant virus, although resistance was generally weak. Kucher (2003) reported that 16% of seroconverters in 2002 had resistant virus and a multidrug resistant virus was first detected in a seroconverter.

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 phenotypic 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 classes 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 resistant 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%.

Chaix studied 108 seroconverters identified in France during 1999 and found 6.5% had NRTI resistant HIV, 3.7% with NNRTI resistance and 2.8% with PI resistance.

Bielawski (2003) reported 6.25% of treatment-naive patients in Poland were infected with virus which contained primary resistance mutations.

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 multidrug resistant isolates were identified.

References

Barbour JD et al. Persistence of primary drug resistance among recently HIV-1 infected adults. AIDS 18: 1683-1689, 2004.

Becker M et al. HIV-1 genotypic resistance in treatment-naive subjects enrolled in an observational trial (GAIN). Antivir Ther 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.

Bezemer D et al. No recent transmission of drug-resistant HIV and non-B subtypes in the Amsterdam cohort studies. Antivir Ther 8: S403, 2003.

Bhaskaran K et al. Do patients who are infected with drug-resistant HIV have a different CD4 cell decline after seroconversion? An exploratory analysis in the UK Register of HIV Seroconverters. AIDS 18: 1471-1473, 2004.

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.

Blick G et al. "Patient zero": the Connecticut source of the multi-drug-resistant, dual-tropic, rapidly progressing HIV-1 strain found in NYC. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract MoOa0101, 2005.

Boden D et al. Resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrobial Agents Chemother, 1998.

Boden D et al. HIV-1 drug resistance in newly infected individuals. Journal JAMA 282: 1135-1141, 1999.

Booth C et al. Divergent pol sequences as markers of HIV-1 superinfection in a case of recurrent acute seroconversion illness. Fourth European Drug Resistance Workshop, Monte Carlo, abstract 101, 2006.

Brenner B et al. Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Investigators of the Quebec Primary Infection Study. Int J Antimicrobial Agents 16: 429-434, 2000.

Brenner BG et al. Persistence and fitness of multidrug resistant human immunodeficiency virus type 1 acquired in primary infection. J Virol 76: 1753-1761, 2002.

Brenner B et al. Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection. AIDS 18: 1653-1660, 2004.

Brindeiro RM et al. Brazilian Network for HIV Drug Resistance Surveillance (HIV-BResNet): a survey of chronically infected individuals. AIDS 17: 1063-1069, 2003.

Briones C et al. Primary genotypic and phenotypic HIV-1 drug resistance in recent seroconverters in Madrid. J Acquir Immune Defic Syndr 26: 145-150, 2001.

Cane P et al. Persistence of primary genotypic resistance following HIV-1 seroconversion for as long as three years post-infection. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 684, 2004.

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. Antivir Ther 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. Antivir Ther 7: S47, 2002.

Chakraborty B et al. Can HIV-1 superinfection compromise antiviral therapy? AIDS 18: 132-134, 2004.

Cohen and Fauci. Transmission of multidrug-resistant human immunodeficiency virus -- the wake-up call. N Engl J Med 339: 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, 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, 2000.

Delaugerre C et al. Persistence of HIV-1 multidrug resistance without any antiretroviral treatment 2 years after sexual transmission. Antivir Ther 8: S201, 2003.

de Mendoza C et al. Decline in the rate of genotypic resistance to antiretroviral drugs in recent HIV seroconverters in Madrid. AIDS 16: 1830-1832, 2002.

De Mendoza C et al. Impact of drug-resistant HIV viruses on viral load, CD4 counts and CD4 decline in recent seroconverters. Twelfth International HIV Drug Resistance Workshop, Los Cabos, abstract 81, 2003.

De Mendoza C et al. Evidence for differences in the sexual transmission of HIV strains with distinct drug resistance genotypes. Clin Infect Dis 39: 1231-1238, 2004.

DePasquale MP et al. Primary HIV infection: in vivo fitness of pre-therapy resistant mutants and potential for secondary spread of HIV from semen. Antivir Ther 4: S89, 1999.

Descamps D et al. Prevalence of resistance mutations in antiretroviral-naive chronically HIV-infected patients in 1998: a French nationwide study. AIDS 15: 1777-1782, 2001.

Descamps D, Chaix ML, et al. French national sentinel survey of antiretroviral drug resistance in patients with HIV-1 primary infection and in antiretroviral-naﶥ chronically infected patients in 2001-2002. J Acquir Immune Defic Syndr 38: 545-552, 2005.

Duwe S et al. Frequency of genotypic and phenotypic drug-resistant HIV-1 among therapy-naive patients of the German Seroconverter Study. J Acquir Immune Defic Syndr 26: 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: 831-836, 2001.

Eron JJ et al. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS 12: F181-F189, 1998.

Fang G 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.

Fang G et al. Recombination following superinfection by HIV-1. Antivir Ther 8: S202, 2003.

Gottlieb G et al. HIV-1 superinfection in a rapid disease progressor: rapid replacement of the initial strain with the superinfecting virus by natural selection. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 454, 2004.

Grant RM et al. Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA 188: 181-188, 2002.

Grant RM et al. Transmission of drug resistant HIV-1 exhibiting lower replication capacity is associated with higher CD4 cell counts. Antivir Ther 7: S41, 2002.

Grant R et al. High frequency of apparent HIV-1 superinfection in a seroconverter cohort. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 287, 2005.

Harzic M et al. Genotypic drug resistance during HIV-1 primary infection in France (1996-1999): frequency and response to treatment. AIDS 16: 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. Antivir Ther 4: S96, 1999.

Hecht FM et al. Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors. N Engl J Med 339: 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.

Hogg RS et al. Drug resistance is associated with an increased risk of death in patients first starting HAART. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 712, 2005.

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. J Virol 70: 1086-1090, 1996.

Jost S et al. A patient with HIV-1 superinfection. N Engl J Med 347: 731-736, 2002.

Koelsch KK et al. Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus. AIDS, 17: F11-F16, 2003.

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. J Infect Dis 187: 683-686, 2003.

Little S et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA 282: 1142-1149, 1999.

Little SJ. Is transmitted drug resistance in HIV on the rise? Br Med J 322: 1074, 2001.

Little S et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 347: 385-394, 2002.

Little S et al. Persistence of transmitted drug-resistant virus among subjects with primary HIV infection deferring antiretroviral therapy. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 36LB, 2004.

Loveday C et al. High prevalence of multiple drug resistance mutations in a UK HIV/AIDS patient population. AIDS 13: 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.

Markowitz M et al. A case of apparent recent infection with a multi-drug-resistant and dual-tropic HIV-1 in association with rapid progression to AIDS. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 973B, 2005a.

Markowitz M et al. Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report. Lancet 365: 1031-1038, 2005b.

Miller V et al. Prevalence of baseline drug resistance mutations in primary HIV infection patients from the QUEST study. Antivir Ther 4: S98 1999.

Novak RM et al. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis 40: 468-474, 2005.

Pao D et al. Long-term persistence of primary genotypic resistance after HIV-1 seroconversion. J Acquir Immune Defic Syndr 37: 2004.

Paxinos EE et al. Natural variation in susceptibility to non-nucleoside reverse transcriptase inhibitors predates drug availability. Antivir Ther 5: abstract 156, 2000.

Periera A et al. Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden. J Infect Dis 180: 2039-2043, 1999.

Pillay D et al. Detection of drug resistance associated mutations in HIV primary infection within the UK. AIDS 14: 906-908, 2000.

Pillay D et al. The impact of transmitted resistance on time to CD4< 350 cells/ml. Antivir Ther 7: S147, 2002.

Pillay D et al. The effect of transmitted drug resistance on virological response to HAART regimens adjusted for genotypic resistance at baseline. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 685, 2004.

Puig T et al. Prevalence of genotypic resistance to nucleoside analogues and protease inhibitors in Spain. The ERASE-2 Study Group. AIDS 14: 727-732, 2000.

Quigg M et al. Mutations associated with zidovudine resistance in HIV-1 among recent seroconvertors. AIDS 11: 835-836, 1997.

Ravaux I et al. Persistence in HIV-1 protease of resistance mutations in absence of drug selective pressure three years after sexual transmission of a multiclass drug resistant variant. Antivir Ther 8: S415, 2003.

Rinck G et al. Trends in transmitted antiretroviral drug resistance in men who have sex with men attending genitourinary medicine clinics in England, Wales and Northern Ireland. Fifteenth International AIDS Conference, Bangkok, abstract PpC4713, 2004.

Ross L et al. Prevalence of antiretroviral drug resistance and resistance mutations in antiretroviral therapy (ART)-naﶥ HIV-infected individuals from 40 US cities during 2003. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-173, 2004.

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. Antivir Ther 7: S147, 2002.

Routy JP et al. Factors associated with a decrease in the prevalence of drug resistance in newly HIV-1 infected individuals in Montreal. AIDS 18: 2305-2312, 2004.

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: F17-F23, 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. Antivir Ther 7: S149, 2002.

Simon V et al. Evolving patterns of HIV-1 resistance to antiretroviral agents in newly infected individuals. AIDS 16: 1511-1519, 2002.

Smith D et al. Incidence of HIV superinfection following primary infection. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 21, 2004.

Smith DM et al. HIV drug resistance acquired through superinfection. AIDS 19: 1251-1256, 2005.

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. J Med Virol 61: 181-186, 2000.

Taylor S et al. Poor penetration of the male genital tract by HIV-1 protease inhibitors. AIDS 13: 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. Br Med J 322: 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 Chemother 44: 2109-2117, 2000.

Verbiest W et al. Prevalence of HIV-1 drug resistance in antiretroviral-naive patients: a prospective study. AIDS 15: 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: 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. J Infect Dis 182: 330-333, 2000.

Weinstock H et al. The epidemiology of antiretroviral drug resistance among drug-naﶥ HIV-1-infected persons in 10 US cities. J Infect Dis 189: 2174-2181, 2004.

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.

Wensing AMJ et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 192: 958-966, 2005.

Wensing AMJ et al. First representative prospective surveillance data on HIV baseline drug resistance from 17 countries in Europe; the SPREAD-programme. Fourth European HIV Drug Resistance Workshop, Monte Carlo, abstract 1, 2006.

Yerly S et al. Transmission of antiretroviral-drug-resistance HIV-1 variants. Lancet 354: 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.

Yerly S et al. Prevalence of co- and super-infection in IVDUs. Antivir Ther 8: S203, 2003.