he great burden of HIV/AIDS in Africa has led the international community to scale up the search for effective prevention strategies for this hardest-hit region. Appropriately, this has included a focus on developing new tools—especially vaccines and microbicides—that will reduce heterosexual transmission, which accounts for the vast majority of new infections on the continent. Many groups are now working to expand capacity for testing candidate HIV vaccines in Africa and to involve at-risk men and women in these clinical studies.

But in many parts of the world outside Africa, the epidemiological picture of HIV in 2002 is strikingly different. In Russia, Ukraine, Belarus and the Central Asian Republics of Kazakhstan and Tajikistan, and further east in China, Iran, Malaysia, Indonesia and Vietnam, the majority of reported HIV infections and AIDS cases in 2001 arose not from sexual transmission but through needle-sharing behaviors among injecting drug users (IDU). While the numbers of IDU infections in any one country may not be large on a population basis, these states have enormous young populations, many with rapidly rising substance abuse rates. A good example is Vietnam, a country of over 78 million people, where IDU accounted for 88% of all reported HIV infections in 2000 and where heroin trafficking from the Golden Triangle has led to a dramatic increase in use among young Vietnamese (1).

In other places where IDU do not represent the majority of infections, they have nonetheless played important roles in HIV spread. This is true in settings as diverse as Burma and Baltimore, the remote Indian Northeast, and cities and towns in Spain, Italy, the Netherlands and Brazil. IDU-related outbreaks were also key to the initial introduction of HIV into all Asian countries except Cambodia. And they are often crucial to the dissemination of new HIV-1 subtypes and recombinants—for example, the recent explosive spread of subtype A virus in Russia and Ukraine, and a B/C recombinant now epidemic among IDU in southern and western China. Overall, the number of countries reporting HIV infections among IDU to the World Health Organization rose from 52 in 1992 to 114 in the year 2000, underscoring the widening global nature of IDU risk.

Thus the epidemiology of HIV in 2002 tells us that for a vaccine to be truly effective in curbing the global epidemic, it must work against both sexual and IDU transmission. Yet these two routes of infection may require some distinct approaches. Scientifically, we don’t know whether the same set of immune responses will work against both routes. The two certainly do not offer the immune system identical opportunities, since blood-borne transmission bypasses the immune defenses present in the genital tract’s mucosal lining, where the first exposure to sexually transmitted HIV takes place—defenses which may be important contributors to vaccine protection. And from the perspective of clinical trials, IDU populations clearly present their own set of challenges.

Here I argue a few key points from among many issues raised by IDU and AIDS vaccines, and briefly review data bearing on them.

1. We cannot assume that vaccines which prevent or reduce sexual transmission will necessarily work as well against IDU spread. The evidence so far is simply too scant to draw any conclusions one way or the other, and some of the available data suggest potentially important differences—making it imperative to test vaccine candidates against both types of transmission. A vaccine that reduces only sexual transmission would arguably have limited public health impact in 114 countries, especially across Eurasia, and might lead to a scenario in which heterosexual transmission is controlled but outbreaks of HIV continue wherever there is IDU spread.
    
2. There is a widespread perception that IDU make for poor participants in HIV vaccine trials, for several reasons—a view that is contradicted by the data.
    
3. Trial sites could potentially be built onto a number of ongoing projects around the world that are now working with IDU populations. One—the Bangkok sites of VaxGen’s ongoing Phase III vaccine trial involving 2,500 IDU—is already well-established, while others could, with appropriate expansion, become AIDS vaccine trial sites in the future.

Comparing sexual and blood-borne transmission

Vaccine responses and acute infection

Animal models using monkeys challenged with SIV (simian immunodeficiency virus) or related viruses point to some differences between intravenous and mucosal exposure. An important caveat, though, is that it remains unproven how well these models predict what happens with IDU versus sexual transmission in humans.

Nevertheless, studies of experimental vaccines in monkeys suggest that it is often easier to protect against mucosal exposure to SIV than against intravenous (i.v.) challenge. For example, Benson, Franchini and colleagues compared protection induced by an SIV vaccine made in the NYVAC viral vector (2). Looking at 12 vaccinated monkeys challenged i.v. with SIV (strain mac251), they found that all of them became infected. Over time, 4 showed some vaccine protection—they gradually brought SIV replication under control and slowed progression to AIDS—while 8 went on to AIDS. But in 12 vaccinated animals challenged intra-rectally, five seemed to clear the SIV infection completely after showing transient viremia; the other 7 animals progressed to AIDS, although more slowly than those in the i.v. group.

This vaccine—like most of the candidates being developed for humans—most likely confers its partial protection by stimulating the cellular immune responses. For the other arm of the immune system, John Mascola’s group compared how well HIV antibodies can protect animals against i.v. versus mucosal infection. (3). Since there are no vaccine candidates so far that induce broadly neutralizing antibodies, the type thought to offer the most promise, Mascola instead infused 26 monkeys with monoclonal antibodies derived from HIV-infected people. He then infected the animals either i.v. or vaginally with a strain of SHIV (an SIV/HIV hybrid). Again, the results showed somewhat better protection against the vaginal challenge than against i.v. exposure.

What could account for these differences? The answer is unknown, but the immune responses in the genital mucosa are one candidate. Another factor (perhaps related) is time: how fast infection is established after exposure by each of these routes, and how long this gives the immune system to mobilize.

Indeed, evidence that sexual infection takes longer to become established (as measured by the time from infection until peak viral load) comes from a study of i.v.- and vaginally-infected macaques challenged with a pathogenic SHIV (4). Peak load occurred at 7 days for animals exposed through injection—but not until 14 days for monkeys challenged vaginally. Similarly, the severe CD4 T-cell declines seen with this (and other) SHIV strains occurred after 14 days for animals challenged i.v., but not until at least 21 days in the vaginally exposed group. If earlier peak viral loads also occur in IDU, then an effective vaccine for IDU might have to mobilize the immune system faster than for protection against sexual transmission.

However, moving from timing to clinical measures, the differences disappeared: Both i.v.- and mucosally-challenged animals in the above study reached about the same peak viral loads and showed similar clinical findings (such as CD4 decline) as their infections progressed. In humans, there is too little data on viral load shortly after infection (days or weeks) to see an effect of transmission route, although by a few months there appear to be no differences.

This raises an alternative view that, at least for the current generation of vaccines aimed at controlling HIV (rather than completely preventing infection), viral load is what really matters—and if peak load in the blood doesn’t differ between i.v. and sexual transmission, then vaccines may work similarly against both. In other words, "viremia is viremia," as this idea is phrased by Larry Corey (head of the HIV Vaccine Trials Network based in the US), no matter how it originates.

Transmission efficiency

IDU transmission is often perceived as being more efficient than mucosal transmission, but careful analysis of the data suggest that this is not the case.

One source of confusion is that HIV infection through blood and blood products is sometimes grouped with IDU transmission. However, this should be considered separately, since it often involves whole units of infected blood or plasma, while IDU transmission mostly occurs through tiny residual volumes of blood in used injection equipment.

Another reason for the misperception is the rapid spread of HIV among injectors once HIV has been introduced into an IDU population, and the very high rates of infection among IDU worldwide. But the speed of spread is affected by two distinct factors: transmission efficiency per act, and frequency of the risk behavior.

Transmission efficiency per act has been estimated in various ways, most of which rely on modeling techniques. These are summarized in Table 1 (adapted from AIDS Res. Hum. Retroviruses 14 [suppl. 3], S223, 1998). Kaplan and Heimer developed a model for IDU transmission in 1992 which estimated a per-act transmission probability of .0067 per injection. This is somewhat higher than the rate per heterosexual sex, .001/act, but roughly similar to transmission from Thai female sex workers to male clients (.03 -.06) and significantly lower than estimates among heterosexual Kenyan men who also had a genital ulcer (.10/sex act).

These studies must be interpreted with caution, but taken together they suggest that IDU transmission per act is, like sexual transmission, relatively inefficient. The much higher reported rates of hepatitis C (generally over 90%) compared with HIV among IDU cohorts in the US, Thailand, and Amsterdam also lend indirect support to these modeling studies.

But while the probability of transmission may be similar for individual acts, most studies find that heroin addicts inject about 1-3 times per day, and cocaine addicts even more frequently. Few people at sexual risk, sex workers aside, have anywhere near these levels of exposure.

Later clinical course of HIV and AIDS

Several large prospective cohorts have been analyzed for differences in the clinical course of HIV/AIDS by transmission route. Comparing MSM and IDU in the US, there appeared to be somewhat slower progression to AIDS among IDU, although clinical outcomes did not differ strikingly. Whether this will be relevant to vaccines that work by reducing viremia and thereby changing the clinical course to AIDS remains to be tested, along with other unrelated factors that could play a role (such as gender, nutritional and immunological status and possibly HIV-1 subtype differences).

Vaccines against blood-borne diseases: the EIAV example

As an interesting side point, it is worth noting an example of a highly effective vaccine against a blood-borne disease of the immune system. This is the Equine Infectious Anemia Virus (EIAV), an animal retrovirus (in the same visna virus family as HIV and SIV) for which spread by unsterile injection equipment has been documented in veterinary settings. EIAV causes epidemic anemia in horses and ponies, and in nature is spread between horses by the bite of horse flies. Interestingly, the fly is not a host of the virus—the virus has no life cycle stage in the fly—but rather is a mechanical transmission vector whose mouthparts act like a hypodermic needle to spread the virus from horse to horse (5).

It is therefore encouraging that Chinese government scientists developed an EIAV vaccine more than 20 years ago (using Pasteur's method of serial passage in culture to attenuate the virus), and that this vaccine has succeeded in virtually eradicating the disease from China's horse herds (personal communication from Yiming Shao, China).

IDU as participants in HIV vaccine efficacy trials

Do IDU make for poor participants in HIV vaccine trials? Concerns have been raised over low retention rates, high rates of medical exclusion (largely due to hepatitis C infection) and, in the US, low HIV incidence rates.

However, a review of data from the field suggests that IDU are already active and engaged trial participants. The clearest example is Thailand’s ongoing trial of the AIDSVAX^® gp120-based vaccine, which involves 2,500 seronegative IDU in Bangkok’s methadone clinics. Retention in this cohort has been strikingly high, with a reported 1.5% loss to follow-up per year (6). If maintained, this will give an overall retention of well over 90% during the three-year trial, remarkable for any HIV at-risk population. At the same time, despite intensive counseling and harm-reduction measures, there is high and sustained seroincidence among these IDUs, fueled largely by imprisonment of participants on drug-related charges (7).

But important barriers to IDU participation in research do exist. Injection drug use is a highly criminalized and stigmatized behavior globally. IDUs generally face many of the same behavioral and psychological challenges common to substance abusers, but also legal and social harms due to the illegality of the substances they use. Moreover, while several strategies have shown effectiveness in preventing HIV infections in IDU—including harm reduction, needle and syringe exchange programs and substitution therapy such as methadone maintenance therapy (MMT)—use of these tools is forbidden or severely restricted by law in most countries around the world (8, 9). Across Asia, for example, only Hong Kong has both MMT and harm reduction programs for IDU.

Conversely, where harm reduction and MMT are available, as they were to many US IDU in the HIVNET vaccine preparedness studies, seroincidence can be low (10).

In these studies, MSM seroincidence from 1995-1997 was measured at 1.55/100 person-years (PY), while among male IDU, the rate was 0.38/100PY, which many researchers consider too low for efficacy trials. Rates were higher among women IDU, at 1.24/100PY, but this group had the lowest enrollment of all groups in the trial. Retention rates among male IDU were encouraging, at 12.3% loss to follow up over 18 months, similar to MSM. Most of the women IDU participants met the enrollment criteria for both injection and sexual risk, suggesting that their dual risks may make it difficult to analyze the influence of transmission route on vaccine-induced protection in this group.

Where could vaccine trials in IDU be done?

In addition to Bangkok, where there is hard evidence that IDU can be enrolled and retained, there are several other IDU cohorts which could participate in future trials. Also in Thailand, a cohort in Chiang Mai supported by the National Institute of Drug Abuse (NIDA, the NIH institute focused primarily on substance abuse), led by David Celentano and Vinai Suriyanon, found a high, steady seroincidence among 400 IDU of 7.7/100PY (95% confidence interval 5.0-10.4) despite risk reduction counseling, condom promotion, and training in safe injection practices. Virtually all newly infected IDU in this cohort have the same HIV subtype E found in cohorts at sexual risk in Chiang Mai.

Several sites are now being built up in China. The HVTN is supporting a site in Guangxi Province (southern China) together with the HIV Prevention Trials Network (HPTN), which also works in Xinjiang, in China’s far northwest. Both sites are involved in HPTN 039, a cohort development study aimed at assessing retention, seroincidence, and cohort capacity. The same protocol is also underway among IDU in St. Petersburg, Russia, and among IDU in Philadelphia, also with HPTN support.

Elsewhere, a clinical trial in New Delhi, India is testing whether new drug treatments for addiction are a useful HIV prevention tool. The study is a collaboration between SHARAN, an Indian NGO that works with drug users in the city’s slum districts, and researchers at Johns Hopkins, and is supported by NIDA as a possible vaccine trial platform. Groups in Philadelphia and Baltimore have demonstrated high retention and, in Baltimore, sustained seroincidence among young injectors. Other studies involving HIV in IDU are underway in Hanoi, Moscow, Karachi, and several Brazilian cities.

If an HIV vaccine is to help turn the tide against HIV/AIDS, it must be effective against IDU transmission. With appropriate commitment and buildup, IDU cohorts suitable for these trials can be available. Engaging them, in turn, requires expanding partnerships with drug users, NGOs and research groups active with IDU, and the vaccine research community.

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^*Chris Beyrer is associate research professor of epidemiology at the Bloomberg School of Public Health of Johns Hopkins University in Baltimore and a Senior Scientific Liaison for the HIV Vaccine Trials Network. From 1992 to 1997 he served as field director for vaccine preparedness studies (PAVE and HIVNET) at Chiang Mai University, also gathering material for his 1998 book, War in the Blood: Sex, Politics, and AIDS in Southeast Asia. He has retained close ties to the region as subunit principal investigator of the Chiang Mai HVTN trial site and investigator in China and Laos.