Lynn A. Paxton

Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana

BACKGROUND Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain. METHODS We randomly assigned HIV-seronegative men and women to receive either tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or matching placebo once daily. Monthly study visits were scheduled, and participants received a comprehensive package of prevention services, including HIV testing, counseling on adherence to medication, management of sexually transmitted infections, monitoring for adverse events, and individualized counseling on risk reduction; bone mineral density testing was performed semiannually in a subgroup of participants. RESULTS A total of 1219 men and women underwent randomization (45.7% women) and were followed for 1563 person-years (median, 1.1 years; maximum, 3.7 years). Because of low retention and logistic limitations, we concluded the study early and followed enrolled participants through an orderly study closure rather than expanding enrollment. The TDF-FTC group had higher rates of nausea (18.5% vs. 7.1%, P<0.001), vomiting (11.3% vs. 7.1%, P=0.008), and dizziness (15.1% vs. 11.0%, P=0.03) than the placebo group, but the rates of serious adverse events were similar (P=0.90). Participants who received TDF-FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF-FTC group who had had an unrecognized acute HIV infection at enrollment. In a modified intention-to-treat analysis that included the 33 participants who became infected during the study (9 in the TDF-FTC group and 24 in the placebo group; 1.2 and 3.1 infections per 100 person-years, respectively), the efficacy of TDF-FTC was 62.2% (95% confidence interval, 21.5 to 83.4; P=0.03). CONCLUSIONS Daily TDF-FTC prophylaxis prevented HIV infection in sexually active heterosexual adults. The long-term safety of daily TDF-FTC prophylaxis, including the effect on bone mineral density, remains unknown. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health; TDF2 ClinicalTrials.gov number, NCT00448669.).

Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users. METHODS In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20-60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00119106. FINDINGS Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0·35 per 100 person-years) and 33 in the placebo group (0·68 per 100 person-years), indicating a 48·9% reduction in HIV incidence (95% CI 9·6-72·2; p=0·01). The occurrence of serious adverse events was much the same between the two groups (p=0·35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0·002). INTERPRETATION In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs. FUNDING US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.

Narrative Review: Antiretroviral Therapy to Prevent the Sexual Transmission of HIV-1

The magnitude of the HIV epidemic has exceeded the worst early predictions. At the end of 2005, the Joint United Nations Programme on HIV/AIDS (UNAIDS) (1) estimated that 38.6 million persons were infected worldwide (4.1 million were incident HIV cases) and that 2.8 million HIV-related deaths occurred in that year alone. Currently, no vaccine to prevent HIV exists and it is unlikely that one will be developed during the next few years. Accordingly, a series of other preventive measures embracing a combination of biological and behavioral approaches have been and are being explored, with some demonstrable positive results (2, 3). Among prevention options, the use of antiretroviral therapy (ART) is particularly attractive because antibiotics have successfully stopped the spread of many other diseases. Antiretroviral therapy has dramatically increased survival for HIV-infected patients (4) and prevented vertical transmission of HIV (5). Antiretroviral therapy could be used for preventing sexual transmission of HIV in 3 ways: 1) effective treatment of infected persons to reduce HIV transmission to sexual partners, 2) nonoccupational postexposure prophylaxis, and 3) preexposure prophylaxis. We provide a current view of each approach, including work in progress. Literature Search Strategy We searched the Cochrane Library and PubMed for relevant publications. We searched the Cochrane Library under the topic HIV/AIDS and then limited results by using the term biomedical prevention. We located a proposal to review the safety and efficacy of nonoccupational postexposure prophylaxis that was not yet completed. We searched PubMed by using the terms HIV and antiretroviral in the Medical Subject Heading (MeSH) database and then limited the results by using the terms prevention and control, transmission, and anti-retroviral agents. We reviewed publications retrieved from this search and selected those that we judged to be relevant. The MeSH terms are part of a distinct vocabulary created by the National Library of Medicine to index articles for MEDLINE and PubMed that provides a consistent way to retrieve information using different terminology. We also searched PubMed using the terms post-exposure, pre-exposure, prophylaxis, prevention, PEP, PREP, nPEP, and HIV. We primarily selected articles published within the past 5 years but did not exclude commonly referenced publications outside of this time period. We also reviewed abstracts from the 10th, 11th, 12th, and 13th Clinical Retrovirus and Opportunistic Infections (CROI) Conferences and the XIV and XVI International AIDS Conferences by using the terms mentioned. We included English-language articles only. We excluded studies of children, adolescents, or both, except when these populations were included in studies on nonoccupational postexposure prophylaxis after sexual assault. We selected studies on the effect of ART on HIV transmission among serodiscordant couples if this was a primary aim of the study and on the basis of the studys sample size. We selected population-level epidemiology studies of the effect of ART on HIV transmission if their study designs included sufficient power to determine statistical significance. We chose publications on animal models of postexposure prophylaxis and preexposure prophylaxis for scientific rigor and for the mode of HIV exposure most closely assimilating sexual HIV exposure in humans. We selected publications of observational studies on nonoccupational postexposure prophylaxis if they evaluated at least 1 of the following outcomes: 1) seroconversions, 2) adherence, 3) repeated treatment requests, or 4) effect on behavioral disinhibition. The Table summarizes these publications (615). We excluded solely descriptive articles on the uptake and prescribing practices of nonoccupational postexposure prophylaxis and articles of cost-effectiveness, ethics, policy, and case reports, except for 1 study describing a failure of nonoccupational postexposure prophylaxis. We reviewed all modeling studies but included only a few representative examples because recent studies use similar methods and differ primarily on the basis of data assumptions, as discussed. Table. Studies on Antiretroviral Nonoccupational Postexposure Prophylaxis* Using ART to Reduce Infectiousness Researchers have extensively studied the probability of sexual transmission of HIV (16). Transmission of HIV depends on the infectiousness of the host and the susceptibility of the sexual partner. Sexual transmission of HIV has been most closely linked to blood viral burden in the infected host (17, 18), which probably serves as a surrogate for HIV concentration in the genital tract (19). In a landmark study (18) of 415 serodiscordant couples conducted in Uganda, the probability of HIV transmission increased directly with blood HIV RNA concentrations. Increased transmission was not observed when HIV RNA level was less than 1500 copies/mL (18). Other studies confirm this observation (20, 21). In addition, a disproportionate number of incident cases of HIV occur with acute or early infection (22), probably because of the high viral burden associated with this stage of infection (23). Researchers have demonstrated increased genital tract shedding of HIV-1 during acute HIV infection (23, 24) and with concurrent sexually transmitted infections (2527). Antiretroviral therapy can be expected to reduce HIV RNA concentrations in blood and seminal plasma (28), female genital tract secretions (29), and rectal secretions (30). Therefore, by extension, ART would be expected to reduce infectiousness when used for treatment. However, the success of such therapy depends on the sensitivity of the virus to the agents selected, patient adherence, and the patients long-term commitment to therapy. Although some studies have shown durable longitudinal suppression of HIV (28, 31), others have demonstrated breakthrough genital tract HIV shedding (32). In addition, the magnitude of HIV suppression can be expected to reflect the differential penetration of antiviral agents into the male and female genital tracts. Accordingly, large differences between the pharmacology of antiretroviral agents in the male and female genital tracts deserve special attention (Figure 1) (31, 3341). Figure 1. Antiretroviral drug concentrations in the male and female genital tract relative to blood plasma concentrations (ratio of genital to blood plasma concentrations). Data from references 31 and 33 to 41. 3TC = lamivudine; ABC = abacavir; APV = amprenavir; ATV = atazanavir; d4T = stavudine; ddI = didanosine; DLV = delavirdine; EFV = efavirenz; ENF = enfuvirtide; FI = fusion inhibitor; FTC = emtricitabine; IDV = indinavir; LPV = lopinavir; ND = not detected; NFV = nelfinavir; NNRTI = nonnucleoside reverse transcriptase inhibitor; N(t)RTI = nucleotide reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RTV = ritonavir; SQV = saquinavir; TDF = tenofovir; ZDV = zidovudine. Penetration of antiviral agents into genital tract secretions is dictated by the degree of protein binding and by a drugs affinity for albumin and 1-acid glycoprotein. Highly protein-bound drugs (>80%) are recovered in lower concentrations in genital tract secretions compared with those in blood plasma. For example, male and female genital tract concentrations of protease inhibitors, with the exception of indinavir, are less than 10% and 50% of blood plasma, respectively. The limited penetration of protease inhibitors into the genital tract probably explains earlier reports of protease resistance in HIV isolates from seminal plasma and vaginal lavage fluid (33, 42, 43). Conversely, most nucleoside and nucleotide reverse transcriptase inhibitors, which have limited protein binding, attain genital tract concentrations that are 2- to 6-fold greater than plasma concentrations (Figure 1) (31, 3341). In addition, the active component of the nucleosides and nucleotides is the phosphorylated intracellular form and not the parent drug routinely measured. Data are available for the levels of intracellular phosphorylated forms of tenofovir, zidovudine, and lamivudine in mononuclear cells isolated from the male genital tract (34, 35). Intracellular tenofovir diphosphate concentrations are 5 to 10 times higher in male genital tract mononuclear cells than in peripheral blood mononuclear cells, whereas lamivudine triphosphate concentrations are similar to peripheral blood mononuclear cell concentrations. Zidovudine triphosphate concentrations are approximately 50% of peripheral blood mononuclear cell concentrations. The critical question is, of course, whether therapy that effectively suppresses HIV replication in the genital tract will prevent sexual transmission of HIV. To date, 2 lines of evidence have been explored to study this question: retrospective and prospective evaluation of HIV transmission in serodiscordant couples and population-level epidemiology studies. Musicco and colleagues (44) studied HIV transmission in 436 serodiscordant couples. A few men (15%) with more advanced disease took zidovudine and had a decrease in the relative risk for HIV transmission to a female sexual partner (odds ratio, 0.5 [95% CI, 0.1 to 0.9]). Castilla and colleagues (45) evaluated HIV transmission in 393 couples during prehighly active antiretroviral therapy (HAART), early HAART, and post-HAART periods (1991 to 2002) and observed an 80% reduction in HIV transmission after introduction of HAART (odds ratio, 0.14 [CI, 0.03 to 0.66]). More recently, Kayitenkore and colleagues (46) reported on HIV transmission in a cohort of 1034 serodiscordant couples from Zambia and Rwanda. In 248 couples, index partners received ART because CD4+ T-cell counts were less than 0.200109 cells/L. Only 2 of 42 partners who acquired HIV infection since 2003 had an HIV-positive partner who received ART. This is fewer than that occurring in the rest of the cohort (odds ratio, 0.19 [C

Chemoprophylaxis with Tenofovir Disoproxil Fumarate Provided Partial Protection against Infection with Simian Human Immunodeficiency Virus in Macaques Given Multiple Virus Challenges

We examined the efficacy of tenofovir disoproxil fumarate (TDF) in blocking simian human immunodeficiency virus (SHIV) infection in Chinese rhesus macaques. Once weekly for 14 weeks or until a macaque became infected, 12 male macaques were inoculated intrarectally with amounts of SHIV(SF162P3) (10 median tissue culture infective doses; 3.8 x 10(5) virus particles) that were approximately 5-fold higher than the human immunodeficiency virus type 1 RNA levels noted in human semen during an acute infection. Of the 12 macaques, 4 received oral TDF daily, 4 received oral TDF once weekly, and 4 (control animals) received no TDF. The control animals became infected after receiving a median of 1.5 virus inoculations; macaques receiving TDF daily (1 macaque remained uninfected after 14 inoculations) and those receiving TDF weekly became infected after a median duration of 6.0 and 7.0 weeks, respectively. Although infection was delayed in treated macaques, compared with control macaques, the differences were not statistically significant (P=.315); however, the study was limited by the small numbers of animals evaluated and the variability in blood levels of TDF that resulted from oral dosing. These data demonstrate that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.

Intermittent Prophylaxis with Oral Truvada Protects Macaques from Rectal SHIV Infection

Treating monkeys with single doses of an antiretroviral drug before and after exposure to SHIV provides protection against infection, a schedule that may prove practical in humans. Rearranging Retroviral Regimens for HIV Antiretroviral drugs have transformed the lives of HIV-infected people by preventing progression to full-blown AIDS. These drugs also dramatically reduce HIV transmission from mothers to infants during pregnancy and breastfeeding, and work in monkeys suggests that daily doses can also reduce transmission from unprotected sex. But prophylactic treatment with antiretroviral drugs is costly and impractical—even if confined to a high-risk population. García-Lerma et al. now show that in monkeys a more realistic medication schedule may work just as well as daily doses. To simulate how people are likely to be infected with HIV, the authors exposed macaque monkeys rectally to 14 weekly doses of simian-human immunodeficiency virus (SHIV) engineered to resemble the human virus. Control macaques treated in this way became infected within the first five exposures to SHIV. Researchers then assessed whether oral, human-equivalent doses of antiretroviral agents could prevent infection in monkeys. The best protection—equivalent to that provided by daily antivirals—occurred when the drug Truvada was given 1, 3, or 7 days before virus exposure followed by a second dose 2 hours after exposure. Less effective, but still better than no treatment at all, was a schedule in which the drug was given 2 hours before or after exposure and then again 24 hours later. Drugs given only 24 or 48 hours after exposure did not safeguard against infection. The results of this study are preliminary, largely because each of the groups had only six macaques, but they are nevertheless promising. If ongoing clinical trials in healthy people show that daily antiretroviral therapy can diminish the chances of acquiring HIV after exposure, a reasonable next step would be to evaluate more practical, less costly drug schedules in humans. For example, a weekly dose followed by a second dose after a possible exposure could prove both effective and tractable. It will also be important to evaluate treatments based solely on exposure, as these would not require ongoing prophylactic drug treatment and would minimize any drug toxicity. If one or more of these therapeutic regimens is successful, antiretroviral drugs may expand the transformation they have already engendered by preventing many more new infections as well as controlling existing ones. HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.

Preclinical Testing of Candidate Topical Microbicides for Anti-Human Immunodeficiency Virus Type 1 Activity and Tissue Toxicity in a Human Cervical Explant Culture

ABSTRACT A human cervical explant culture was utilized for the preclinical assessment of anti-human immunodeficiency virus type 1 (HIV-1) activity and tissue toxicity of formulated, candidate topical microbicides. Products tested included cellulose acetate 1,2-benzene dicarboxylate (CAP), a carrageenan-based product (PC-515), a naphthalene sulfonate polymer (PRO 2000), a lysine dendrimer (SPL7013), a nonnucleoside reverse transcriptase inhibitor (UC781), and an antimicrobial peptide (D2A21), along with their placebos. Cervical explants were cultured overnight with HIV-1 with or without product, washed, and monitored for signs of HIV-1 infection. HIV-1 infection was determined by p24gag levels in the basolateral medium and by immunohistochemical analysis of the explant. Product toxicity was measured by the MTT [1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan] assay and histology. CAP, PRO 2000, SPL7013, and UC781 consistently prevented HIV-1 infection in all explants tested. PC-515 and D2A21 prevented HIV-1 infection in 50% or fewer of the explants tested. Placebos did not prevent infection in any of the explants tested. With the exception of PRO 2000 (4%), the MTT assay and histological analysis of the other products and placebos showed minimal toxicity to the epithelium and submucosa. Collectively, these data suggest that this culture system can be used for evaluating the safety and efficacy of topical microbicides designed for vaginal use.

In Vitro Comparison of Topical Microbicides for Prevention of Human Immunodeficiency Virus Type 1 Transmission

ABSTRACT A standardized protocol was used to compare cellular toxicities and anti-human immunodeficiency virus type 1 (HIV-1) activities of candidate microbicides formulated for human use. The microbicides evaluated were cellulose acetate phthalate (CAP), Carraguard, K-Y plus nonoxynol-9 (KY-N9), PRO 2000 (0.5 and 4%), SPL7013 (5%), UC781 (0.1 and 1%), and Vena Gel, along with their accompanying placebos. Products were evaluated for toxicity on cervical and colorectal epithelial cell lines, peripheral blood mononuclear cells (PBMCs), and macrophages (MΦ) by using an ATP release assay, and they were tested for their effect on transepithelial resistance (TER) of polarized epithelial monolayers. Anti-HIV-1 activity was evaluated in assays for transfer of infectious HIV-1 from epithelial cells to activated PBMCs and for PBMC and MΦ infection. CAP, Carraguard, PRO 2000, SPL7013, and UC781 along with their placebos were 20- to 50-fold less toxic than KY-N9 and Vena Gel. None of the nontoxic product concentrations disrupted the TER. Transfer of HIV-1Ba-L from epithelial cells to PBMCs and PBMC and MΦ infection with laboratory-adapted HIV-1Ba-L and HIV-1LAI isolates were inhibited by all products except Carraguard, KY-N9, and Vena Gel. KY-N9, Vena Gel, and Carraguard were not effective in blocking PBMC infection with primary HIV-1A, HIV-1C, and HIV-1CRF01-AE isolates. The concordance of these toxicity results with those previously reported indicates that our protocol may be useful for predicting toxicity in vivo. Moreover, our systematic anti-HIV-1 testing provides a rational basis for making better informed decisions about which products to consider for clinical trials.

A Human Colorectal Explant Culture to Evaluate Topical Microbicides for the Prevention of HIV Infection

A human colorectal explant culture was developed to assess the safety and efficacy of topical microbicides proposed for use in humans. Because any product marketed for vaginal application will likely be used for anal intercourse, it is important to evaluate these products in colorectal explant tissue. Microbicides tested included cellulose acetate 1,2-benzenedicarboxylate (CAP), PRO 2000, SPL7013, Vena Gel, and UC781, along with their accompanying placebos. Colorectal tissues were exposed to microbicides overnight and either fixed in formalin to evaluate toxicity by histological analysis or placed in 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) to quantitatively determine tissue viability. Histological analysis showed minimal toxicity for CAP, UC781, and Vena Gel. Shedding of epithelium with intact lamina propria occurred for the PRO 2000 and SPL7013 products, and shedding of epithelium and necrosis of the lamina propria occurred in explants cultured with nonoxynol-9. The MTT assay confirmed these results for PRO 2000 (4% and 0.5%), SPL7013 (and placebo), and nonoxynol-9 but also demonstrated reduced viability for CAP. However, viability of tissues treated with all products was not significantly different from that of the medium control. Efficacy of the microbicides was evaluated by measuring human immunodeficiency virus type 1 (HIV-1) infection of explants in the absence or presence of products. All microbicide formulations tested were highly effective in preventing HIV infection. However, explants treated with some of the placebo formulations also exhibited a lower level of infection. Most of the products developed for vaginal application showed minimal toxicity and were effective in reducing HIV-1 infection in colorectal tissues. These results suggest that this model is useful for evaluating the safety and efficacy of topical microbicides when used rectally.

Pre-exposure prophylaxis for HIV infection: what if it works?

For all the advances in treatment of HIV infection, the mainstays of prevention have changed little: sexual abstinence, condoms, sterile injection equipment, avoidance of high-risk behaviours, and knowing one’s own serostatus and that of any sexual or drug-injecting partners. Although these strategies can be eff ective and recent years have seen decreases in new infections in some countries and in some risk groups, the 11 000 new infections daily is ample testament that additional methods of prevention are needed. Evidence for successful HIV-prevention technologies is mixed. Randomised studies of male circumcision in South Africa, Kenya, and Uganda were discontinued early after interim review showed reductions in new HIV infections ranging from 60% to 74% in the circumcised men compared with those who were not circumcised. Several topical microbicides are in advanced trials. However, phase III trials of C-31G (originally developed by Cellegy Pharmaceuticals) and cellulose sulphate (Polydex Pharmaceuticals, Nassau, Bahamas) were terminated early because preliminary results suggested no effi cacy (C-31G) or increased risk of HIV transmission (cellulose sulphate). HIV-vaccine research continues despite two completed trials of AidsVax (VaxGen, South San Francisco, CA, USA) that showed no effi cacy. Proof of effi cacy of any present microbicide or vaccine candidate is several years away, and fi rst products will probably be only moderately eff ective. The need to manufacture such a product in large quantities and distribute it around the world will pose additional challenges.

Update and Overview of Practical Epidemiologic Aspects of HIV/AIDS among Injection Drug Users in the United States

In a changing public health landscape in which local, state, and federal agencies must confront threats of bioterrorism, emerging infections, and numerous chronic diseases, transmission of HIV among injection drug users (IDUs) continues to be an important public health issue and one of the driving forces behind the HIV epidemic. Using a computerized MEDLINE search of published articles from January 1981 through October 2005, we conducted a literature review of practical epidemiologic aspects of HIV/AIDS among IDUs in the United States. Although recent trends indicate a decline in the proportion of newly diagnosed HIV infections associated with injection drug use, drug-use behaviors overall still account for 32% of new HIV diagnoses. Factors in addition to syringe sharing contribute to HIV transmission among IDUs: risky sexual behaviors, sharing of drug preparation equipment and drug solutions, and contextual and social factors. Promising approaches for HIV prevention include rapid HIV testing, office-based substance abuse treatment, behavioral interventions, improved communication about syringe exchange programs, and case management. HIV among IDUs continues to be an important public health problem in the 21st century. It is imperative that public health agencies continue to monitor and combat the HIV epidemic among IDUs to ensure that hard-won gains will not be eroded.