Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009.
We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27).
Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.
Citation: Jain V, Liegler T, Vittinghoff E, Hartogensis W, Bacchetti P, et al. (2010) Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009. PLoS ONE 5(12): e15510. doi:10.1371/journal.pone.0015510
Editor: Zhiwei Chen, The University of Hong Kong, Hong Kong
Received: July 29, 2010; Accepted: October 6, 2010; Published: December 10, 2010
Copyright: © 2010 Jain et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: National Institutes of Health, National Institute of Allergy and Infectious Diseases (T32 AI060530, PO1 AI071713 to FMH, and K24AI069994 to SGD). This work was also supported in part by the University of California San Francisco Center for AIDS Research (P30 AI027763) and the University of California San Francisco Clinical and Translational Science Institute (UL1 RR024131). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Transmitted drug-resistant (TDR) HIV is an ongoing public health challenge, affecting approximately 7–21% of new HIV infections in the United States and Europe –. Understanding current TDR patterns can help clinicians assess the importance of genotyping antiretroviral therapy (ART)-naïve patients, inform the selection of ART regimens, and anticipate trends that may affect our future ability to effectively treat the HIV epidemic with existing ART agents.
There are two important sources of TDR: (1) persons who develop drug resistance mutations while on ART and subsequently transmit HIV and (2) persons who acquire TDR mutations during initial infection and maintain the mutations in the absence of ART until they transmit HIV. If TDR trends are driven primarily by persons with drug-resistant HIV who are viremic despite taking ART, changes in ART that achieve better suppression of drug-resistant HIV should rapidly decrease TDR rates. In contrast, if TDR is driven more by ART-naïve individuals, the effects of novel therapies should be minimal or delayed, at least during the initial period that these drugs become widely available.
Treatment options for patients with drug-resistant HIV changed dramatically from 2007–2008. Boosted darunavir and etravirine both showed strong efficacy in clinical trials –, and two medications representing novel ART classes—raltegravir and maraviroc , —became widely available in the United States and particularly in San Francisco, aided by universal ART access programs.
Although the full clinical impact of these new drugs remains undefined, emerging data suggest that the remarkable efficacy displayed in clinical trials—particularly with raltegravir —is also being observed in routine care . Consistent with these reports, investigators in San Francisco recently reported that from 2004–2008, the city-wide virologic suppression rate improved from 48% to 78% . These investigators also developed a novel population-level HIV risk measure termed “community viral load”—defined as the mean of all persons' most recent HIV plasma RNA levels—and reported that community viral load declined substantially from 2004–2008 period .
A recent mathematical modeling study of TDR in San Francisco, however, projected that NNRTI drug resistance would increase over the next five years, primarily from transmission by ART-naïve individuals . Thus far, it has not been possible to compare predictions from this modeling study to actual patient-based observational data from 2008 and 2009.
The effect of the newest ART medications on the transmission of drug-resistant HIV is not known. We therefore analyzed HIV genotypes among patients with acute/early HIV in San Francisco, with a primary objective of estimating the prevalence of TDR in an urban setting with historically high levels of drug resistance . Our secondary objective was to compare the prevalence of TDR before and after the introduction of new antiretroviral agents in late 2007.
The Committee on Human Research (CHR) is the institutional review board for the University of California, San Francisco and its affiliates, FWA00000068. The CHR approved this study, which involves human subjects as research subjects, entitled “The Options Project: An Observational Study of Individuals Recently Infected with HIV-1.” This study was given approval number H7429-11471-16, which expires 07 May 2011. All participants gave informed written consent for participation.
Study population and setting
We studied enrollees in the Options Project (San Francisco General Hospital, University of California, San Francisco) with estimated HIV infection dates from 2002–2009. The Options Project is a cohort study of individuals enrolled within 12 months of HIV antibody seroconversion (in 2003, this was restricted to within 6 months of seroconversion). Most participants are referred by community providers if acute (<1 month) or early (<6 months) HIV infection is suspected. Remaining participants directly seek screening, or are referred from community-based organizations and HIV testing sites. Participants are enrolled if they meet screening criteria for acute/early HIV that combine clinical history, serologic testing, and plasma HIV RNA determination as described previously , . Briefly, participants were defined as having acute/early HIV if they met one or more of the following three criteria: (1) two plasma HIV-1 RNA levels ≥3,000 copies/mm3 with a negative or indeterminate HIV-1 antibody test; (2) a positive HIV-1 antibody test, with a history of a negative HIV-1 antibody test within the previous 12 months (in 2003, this was changed to 6 months); or (3) a clinical history suggestive of recent HIV-1 acquisition, along with a reactive standard HIV-1 antibody test, but a nonreactive less-sensitive (“de-tuned”) HIV-1 antibody test , .
Clinical and laboratory evaluations
Study participants had demographic and behavioral data collected via standardized interviews by trained counselors. CD4 cell counts and plasma HIV-1 RNA levels were also measured.
HIV-1 population sequence genotypes were determined on all participants (TRUGENE system, Siemens Healthcare Diagnostics, Tarrytown, NY) as described previously , . Initial genotypes were included for analysis if performed within 90 days of screening for cohort entry. For individuals who initiated ART during early HIV infection, genotypes were analyzed only if done within 10 days of initiating ART. Drug resistance was ascertained using published guidelines . These guidelines optimize the specificity of TDR classification for epidemiologic studies by including only mutations that are rarely selected for without drug pressure, and by excluding common polymorphic mutations.
The overall prevalence of TDR was calculated by estimated year of infection, along with exact binomial 95% confidence intervals. Resistance to each ART class (nucleoside reverse transcriptase inhibitors [NRTIs], NNRTIs, and PIs) was also calculated by year.
To compare the odds of TDR before and after new antiretroviral medications arrived in late 2007, we divided patients into two groups by estimated dates of HIV infection (2005–2007 vs. 2008–2009). Logistic regression of TDR was performed on this binary time period predictor. Several other predictors of TDR were also examined in unadjusted analyses, including age, injection drug use <2 months prior to cohort enrollment, sexual identity (MSM, male non-MSM, or female), and estimated duration of HIV infection upon specimen collection.
A total of 372 patients enrolled in the Options cohort from 2002–2009 and had baseline genotyping. Overall, 95% were male, with a median age of 35 years (IQR 30–40 years); 96% were men who have sex with men (MSM), and 9% used injection drugs. The median CD4 cell count at diagnosis was 520 cells/mm3 (IQR 391-660 cells/mm3); median plasma HIV RNA level was 59,854 copies/mm3 (IQR 9,775–404,885 copies/mm3).
From 2002–2009, 59 of 372 patients (16%) had transmitted HIV-1 drug resistance mutations. The prevalence of TDR was 19% in 2002, dropped to 7% in 2003, then rose from 2003–2007, reaching a peak of 24% in 2007 (Fig. 1A). Drug resistance was then 15% in 2008, and was also 15% in 2009. NRTI resistance fluctuated substantially, rising from 6% in 2002–2003 to 16% in 2006, then decreasing to 11% in 2009 (Fig. 1B). NNRTI resistance increased from 5% in 2002–2003 to 13% in 2007, and was 8% in 2009 (Fig. 1C). PI resistance was 15% in 2002, but was lower from 2003–2009, ranging from 4–6% (Fig. 1D).
Prevalence (dot) and 95% confidence interval (vertical line) of overall transmitted drug resistance (A), NRTI resistance (B), NNRTI resistance (C), and PI resistance (D). TDR, transmitted drug resistance; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
We examined whether TDR differed before and after the arrival of new antiretroviral medications in late 2007. From 2008–2009, 15% (95% CI 9%–25%) of cohort members acquired TDR. This was lower than the 22% prevalence seen in 2005–2007 (95% CI 14%–30%), but the confidence intervals around both point estimates were wide. The odds of TDR was lower in 2008–2009 compared to 2005–2007, but this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27). In unadjusted analyses, age, sexual identity (MSM, male non-MSM, or female), duration of HIV infection, and recent injection drug use all had little association with TDR and did not reach statistical significance, but confidence intervals were too wide to rule out the possibility of substantial associations (data not shown).
We found that despite the introduction of novel ART agents in San Francisco starting in late 2007, including raltegravir, maraviroc, and etravirine, the prevalence of transmitted drug resistance in 2008–2009 remained substantial and was not significantly different than in prior years.
To our knowledge, this is the first report of TDR among persons infected with HIV in 2008–2009, after the newest ART medications arrived. Among patients infected in 2005–2007, Hurt et al. reported a 21% prevalence of TDR in North Carolina, similar to our estimate . Numerous reports exist on TDR trends among persons with chronic HIV, but the impact of new ART is difficult to assess using these data as they can reflect HIV acquisition years before HIV diagnosis.
Our finding that TDR remained substantial in 2008–2009 could have multiple explanations. It is unlikely that new ART medications have inadequate potency given their demonstrated efficacy in treating drug-resistant HIV –, , . Therefore one explanation for our findings is that suboptimal engagement in medical care and/or poor ART adherence could be limiting the penetration of new ART medications among TDR source patients, leading to a persistently elevated TDR rate. However, recent data from San Francisco investigators demonstrates that virologic suppression is improving, and circulating levels of viremia are decreasing, arguing against poor engagement in care or poor adherence as chief explanations for our results .
A second explanation of our findings is that a sizeable fraction of drug-resistant HIV is being transmitted by treatment-naïve persons who themselves acquired TDR. Given that several years typically elapse between HIV infection and diagnosis, ART-naïve individuals have ample time to transmit drug resistance mutations to new recipients. Additionally, persons with early stage HIV are the least likely to be on ART, yet may be responsible for a large fraction of forward transmission events . Furthermore, persons with acute/early HIV may have higher seminal HIV RNA levels, and thus higher infectivity . In this scenario—where TDR is largely transmitted by ART-naïve persons—the effects of novel ART regimens on TDR rates may be delayed.
The TDR prevalence we observed in recent years differs from that predicted by the mathematical model of Smith et al. , who had predicted rising NNRTI resistance from 2008–2009. In contrast, our results suggest a stable or even decreasing prevalence of transmitted NNRTI resistance in San Francisco. While the sophisticated aforementioned model provides important insights into TDR patterns, it did not appear to account for changes in HIV treatment options afforded by the newest ART medications, possibly explaining the differences in results.
Our analysis includes several important limitations. First, our acute/early HIV cohort is not a representative population-based sample. As such, our results may not fully reflect the HIV epidemic in San Francisco, though the demographic characteristics of our cohort subjects closely mirror those of the San Francisco epidemic overall. Since our study focused on one geographic area, there are likely to be differences in TDR rates in other settings, particularly in resource-limited regions where treatment options differ substantially. Second, we lack data on the uptake of new ART medications in San Francisco, information which might best be obtained through clinical databases of treatment records but which was not available for this analysis. If the uptake of new ART agents has been slow, more time may be needed to assess the impact on TDR. Third, our results should be interpreted with caution given the wide confidence intervals surrounding the annual estimates for TDR. Studies with longer duration sampling across broader geographic areas may allow better comparisons of TDR before and after the introduction of new ART agents.
Despite these limitations our data provide potential insights into drug-resistant HIV transmission in a setting with historically high levels of drug resistance. Despite the arrival of several novel ART medications beginning in late 2007, the prevalence of TDR remains substantial at the current time. This emphasizes that early diagnosis and aggressive treatment strategies for patients with drug-resistant HIV remain crucial. Continued surveillance will be essential in fully understanding the impact new ART agents will have on TDR epidemiology.
We are grateful to Timothy Schmidt and Jacqueline Javier in the laboratory for core virology, AIDS Research Institute, UCSF for genotyping expertise, and to Gerald Spotts for database management expertise. We thank the patients of the Options and SCOPE cohorts for their generous participation in ongoing studies. Parts of this work were presented by in poster format at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) on February 8–11, 2009 in Montreal, Canada.
Conceived and designed the experiments: VJ SGD FMH. Performed the experiments: TL. Analyzed the data: VJ WH EV PB SGD FMH. Contributed reagents/materials/analysis tools: TL. Wrote the paper: VJ SGD FMH. Contributed to manuscript revision: LP LL CDP RMG.
- 1. Hurt CB, McCoy SI, Kuruc J, Nelson JA, Kerkau M, et al. (2009) Transmitted antiretroviral drug resistance among acute and recent HIV infections in North Carolina from 1998 to 2007. Antivir Ther 14: 673–678.
- 2. Weinstock HS, Zaidi I, Heneine W, Bennett D, Garcia-Lerma JG, et al. (2004) The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis 189: 2174–2180.
- 3. Chaix M-L, Descamps D, Wirden M, Bocket L, Delaugerre C, et al. (2009) Stable frequency of HIV-1 transmitted drug resistance in patients at the time of primary infection over 1996-2006 in France. AIDS 23: 717–724.
- 4. Yerly S, Junier T, Gayet-Ageron A, Amari EB, von Wyl V, et al. (2009) The impact of transmission clusters on primary drug resistance in newly diagnosed HIV-1 infection. AIDS 23: 1415–1423.
- 5. Vercauteren J, Wensing AM, van de Vijver DA, Albert J, Balotta C, et al. (2009) Transmission of drug-resistant HIV-1 is stabilizing in Europe. J Infect Dis 200: 1503–1508.
- 6. Yerly S, von Wyl V, Ledergerber B, Boni J, Schupbach J, et al. (2007) Transmission of HIV-1 drug resistance in Switzerland: a 10-year molecular epidemiology survey. AIDS 21: 2223–2229.
- 7. Haubrich R, Berger D, Chiliade P, Colson A, Conant M, et al. (2007) Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS 21: F11–18.
- 8. Katlama C, Esposito R, Gatell JM, Goffard JC, Grinsztejn B, et al. (2007) Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 21: 395–402.
- 9. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, et al. (2007) Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 370: 39–48.
- 10. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, et al. (2007) Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 370: 29–38.
- 11. Hicks C, Gulick RM (2009) Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis 48: 931–939.
- 12. MacArthur RD, Novak RM (2008) Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. Clin Infect Dis 47: 236–241.
- 13. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, et al. (2008) Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 359: 339–354.
- 14. Scherrer AU, von Wyl V, Fux CA, Opravil M, Bucher HC, et al. (2010) Implementation of raltegravir in routine clinical practice: selection criteria for choosing this drug, virologic response rates, and characteristics of failures. J Acquir Immune Defic Syndr 53: 464–471.
- 15. Das M, Chu PL, Santos GM, Scheer S, Vittinghoff E, McFarland W, Colfax G (2010) Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. PLoS ONE 5: e11068.
- 16. Smith RJ, Okano JT, Kahn JS, Bodine EN, Blower S (2010) Evolutionary dynamics of complex networks of HIV drug-resistant strains: the case of San Francisco. Science 327: 697–701.
- 17. Grant RM, Hecht FM, Warmerdam M, Liu L, Liegler T, et al. (2002) Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA 288: 181–188.
- 18. Hecht FM, Busch MP, Rawal B, Webb M, Rosenberg E, et al. (2002) Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS 16: 1119–1129.
- 19. Barbour JD, Hecht FM, Wrin T, Segal MR, Ramstead CA, et al. (2004) Higher CD4+ T cell counts associated with low viral pol replication capacity among treatment-naive adults in early HIV-1 infection. J Infect Dis 190: 251–256.
- 20. Janssen RS, Satten GA, Stramer SL, Rawal BD, O'Brien TR, et al. (1998) New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. JAMA 280: 42–48.
- 21. Kothe D, Byers RH, Caudill SP, Satten GA, Janssen RS, et al. (2003) Performance characteristics of a new less sensitive HIV-1 enzyme immunoassay for use in estimating HIV seroincidence. J Acquir Immune Defic Syndr 33: 625–634.
- 22. Grant RM, Kuritzkes DR, Johnson VA, Mellors JW, Sullivan JL, et al. (2003) Accuracy of the TRUGENE HIV-1 genotyping kit. J Clin Microbiol 41: 1586–1593.
- 23. Kuritzkes DR, Grant RM, Feorino P, Griswold M, Hoover M, et al. (2003) Performance characteristics of the TRUGENE HIV-1 Genotyping Kit and the Opengene DNA Sequencing System. J Clin Microbiol 41: 1594–1599.
- 24. Shafer RW, Rhee SY, Pillay D, Miller V, Sandstrom P, et al. (2007) HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS 21: 215–223.
- 25. Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, et al. (2008) Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 359: 1429–1441.
- 26. Brenner BG, Roger M, Routy JP, Moisi D, Ntemgwa M, et al. (2007) High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 195: 951–959.
- 27. Pilcher CD, Tien HC, Eron JJ, Vernazza PL, Leu S-Y, et al. (2004) Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 189: 1785–1792.