Table of Contents

• Introduction
• Updated CDC Incidence Data for HIV
• HIV Prevention Methods
• Reducing Exposure to HIV
• Pre-Exposure Prophylaxis (PrEP)
• Treatment as Prevention
• Should HIV Superinfection Be a Concern?
• Summary
• References

Introduction

I'd like to welcome you to a CME/CE-accredited activity on recent developments in HIV prevention, brought to you by The Body PRO.

Most of you have probably heard the news from the CDC [U.S. Centers for Disease Control and Prevention] in August that HIV incidence is much higher than previously thought.¹

Anita Radix, M.D., M.P.H.

Today, I will take a closer look at the updated incidence numbers and which populations are particularly affected. I will also discuss some of the newest strategies that are being investigated for HIV prevention. These include treating sexually transmitted infections, specifically herpes simplex, as a mechanism to reduce HIV transmission and the current status of pre-exposure prophylaxis trials.

I will also discuss the controversial Swiss guidelines concerning the transmission potential of HIV-infected patients on antiretroviral therapy who have undetectable viral loads.²

Updated CDC Incidence Data for HIV

It was at AIDS 2008 [XVII International AIDS Conference] that the CDC chose to announce that the incidence of HIV was much higher than previously thought.³ The incidence of HIV had previously been estimated to be in the area of about 40,000 new infections a year, but this is based on an indirect and probably less accurate method of calculation.⁴ The new technology developed by the CDC says that the incidence of HIV in the United States is about 40% higher than previously reported.

To overcome the limitations of previous HIV monitoring methods, the CDC turned to a testing methodology called "Serological Testing Algorithm for Recent HIV Seroconversion" (or STARHS), which had been developed about five years ago to differentiate between recent and more long-standing infections.⁵

Building on the existing infrastructure of the CDC's national HIV/AIDS case reporting system, researchers used this technology to implement population-based HIV incidence surveillance.³

All patients that had a confirmed HIV diagnosis are tested with a second antibody assay, called a BED assay. The BED assay measures the ratio of anti-HIV IgG relative to total IgG. Because that ratio increases with time following HIV infection, this method can be used to estimate how long a patient has been infected.

Of 6,864 diagnostic specimens tested using the BED assay, 2,133 (31%) were classified as recent infections, meaning that they were believed to have been infected within the last 156 days. Using those figures, researchers estimated that in the 22 states included in the study, about 39,400 persons were diagnosed with HIV in 2006. Nationwide, they found, about 56,300 adolescents and adults were newly infected with HIV in 2006, which translates to an incidence rate of 22.8 per 100,000 persons. It is important to note that this new estimate does not represent an actual increase in the annual number of new HIV infections. In fact, CDC analysis suggests incidence has stabilized since the late 1990s.

The new CDC estimate finds that of all new HIV infections, 27% occurred in women. This reflects stable HIV incidence rates among women in the United States in the last few years. Other recent estimates of HIV and AIDS in women have been similar.⁶

However, the fact that over a quarter of HIV infections were in women is a reflection of women's greater presence in the HIV epidemic, compared to the early years of the epidemic.⁷

Consistent with previously observed trends in HIV transmission,⁶ men who have sex with men [MSM] represented a significantly greater proportion of the estimated new infections in 2006 than any other risk group. MSM accounted for 53% of new HIV infections in 2006 while heterosexuals accounted for 31% and injection drug users for 12% of the estimated new HIV infections.

However, the trend analysis revealed some encouraging news in certain populations. A significant reduction in new HIV infections was seen among injection drug users, for example, and a decline in recent years was seen among heterosexuals. Unfortunately, this same analysis sharply demonstrated that, since the early 1990s, HIV incidence has been steadily increasing among gay and bisexual men, suggesting that current prevention efforts have not been as effective in this group.

When you look at estimated rates of new infections broken down by race and ethnicity, it's dramatically clear that African Americans are disproportionately affected by HIV, with 2006 HIV rates more than seven times as high as that among whites. African Americans accounted for about 45% of new infections in 2006. The incidence of HIV among African Americans peaked in the late 1980s and has continued to exceed the number of infections in whites since that time.

Also, Hispanics accounted for 17% of estimated new HIV infections in 2006 -- a rate three times as high as that among whites. Whites accounted for 35% of new infections in that same year and Asian/Pacific Islanders 2% of new infections.

Despite these differences, incidence rates in all groups have been relatively stable over the last six years. What the new measure of incidence does is to confirm the tremendous racial and ethnic disparities that exist for new HIV infections.

Nothing new was found in terms of the estimated percentage of new HIV infections by age. Young people are still the largest group being diagnosed, with about 34% of new infections in 2006 occurring in people ages 13 to 29, 31% of the infections occurring in people ages 30 to 39, 25% in people ages 40 to 49 and 10% in people older than 50.

That's the summary of the new CDC statistics. As mentioned previously, it's discouraging to note that despite a decade of prevention efforts in the 1990s, the incidence in men who have sex with men has increased, with the highest burden of new cases occurring in this population and in African Americans and Hispanics. Clearly more effective prevention interventions need to be developed that focus on these high-risk groups.

HIV Prevention Methods

So let's now look at some HIV prevention methods. Myron Cohen of the University of North Carolina, Chapel Hill gave a fascinating plenary discussion at AIDS 2008 looking at HIV prevention methods.⁸ He outlined four opportunities for HIV prevention. The first, he said, is what is known as primary prevention, or reducing exposure to HIV. Different techniques have been used for primary prevention, including the promotion of condoms, abstinence and more recently circumcision.

The second and third opportunities for HIV prevention occur either before or after exposure to HIV when strategies are used to prevent infection.

Lastly, there is the effort to reduce infection from a person with HIV through the provision of effective antiretroviral therapy.

In terms of primary prevention methods, we know that both behavioral change and barrier methods are extremely effective when used, but 100% compliance is very difficult to achieve.^9,10 I will therefore focus this discussion on the evidence of antimicrobial and antiretroviral approaches to reduce HIV transmission.

Reducing Exposure to HIV

We know that, in general, transmission of HIV is related to the concentration or level of HIV RNA; that is, the higher the concentration of HIV in the genital tract, the higher the probability of transmission.¹¹

This above slide demonstrates the probability of a transmission event for a given concentration of HIV RNA in semen specimens. As the concentration of HIV RNA increases, the likelihood of transmission also goes up.

However, the probability of HIV transmission is dynamic. It is affected by many factors ,including the specific type of sexual transmission that occurs. Anal intercourse, for example, is a more effective mechanism of transmission than vaginal intercourse.¹² Several studies have also shown that transmission is facilitated by the presence of concurrent sexually transmitted infections.^13,14

Circumcision has been shown to dramatically influence transmission rates.^15,16 However, most of the studies confirming this have been conducted in Africa. We should remember that the HIV epidemic in Africa is very different from the epidemic in the United States. The epidemic in Africa, first of all, is generalized and transmission is predominantly male to female, and occurring in an environment of high HIV prevalence.¹⁷ The U.S. epidemic is concentrated within specific populations, for example, among men who have sex with men.¹

It's important to note that there have not been experimental studies investigating the efficacy of circumcision among MSM. Also, in the United States, circumcision rates are already high, about 70% among adult men.¹⁸ Thus results from these circumcision studies should not be generalized to the U.S. population.

We also need to consider variations in transmission potential over time. Timing is a very important factor in HIV transmission. The risk of HIV transmission is highest during the months immediately after seroconversion and again during advanced HIV or AIDS.¹⁹ The probability of HIV transmission can again rise if an STD [sexually transmitted disease] occurs, causing inflammation of the genital tract and higher genital tract HIV-RNA concentrations.¹²

How much does the presence of an STD raise the risk for HIV transmission? Data, for example, suggest that HSV-2 [herpes simplex virus 2] and HIV-1 infections have synergistic interactions.²⁰ HIV alters the clinical presentation of HSV-2 and the frequency of asymptomatic genital shedding may increase HSV-2 transmission. Also, HSV-2 may have an impact on HIV-1 transmission.

A 2006 meta-analysis of 19 studies by Ester Freeman showed that HSV-2 infected women were about three times more likely to acquire HIV than non HSV-2 infected women.²¹ An increase in risk was also seen among MSM.

HSV-2 appears to increase HIV levels in the plasma and genital tract and thus increase the likelihood of HIV acquisition.

Researchers have been looking at whether the risk of HIV transmission can be modified by the use of antivirals to treat HSV-2 infection in individuals who are involved in high-risk activities. Two studies presented at AIDS 2008 attempted to answer this question. The first was a randomized, double-blind, placebo-controlled trial of HSV-2 suppressive therapy with acyclovir [Zovirax] versus placebo in Tanzania among high-risk women.²²

The second study (HPTN 039) was also a randomized, double-blind, placebo-controlled trial of HSV-2 suppressive therapy with acyclovir versus placebo, but was conducted in different populations that included women from southern Africa and MSM from the United States and Peru.²³

The first study, by Deborah Watson-Jones, screened women for the presence of HSV-2 antibodies and negative HIV status; 821 HSV-2 seropositive, but HIV-negative, women were randomized to acyclovir 400 mg twice a day versus placebo. These women were followed for at least one year.²²

The results of the study were disappointing. Eight percent of the women seroconverted to HIV, both in the placebo group and the acyclovir group. Therefore, in this intention-to-treat study, there was no benefit seen of acyclovir in reducing HIV incidence.

The second study, by Jorge Sanchez, was a very large study known as HPTN 039.²³ There were 1,358 HIV-negative and HSV-2 positive women who were enrolled at three sites in Africa and also 1,814 men who have sex with men -- also HIV-negative and HSV-2 positive -- who were enrolled from the United States and in Peru.

The participants were randomized to receive either acyclovir or placebo and were seen monthly to be given the drug. The researchers also measured adherence and the clients received risk reduction and adherence counseling.

The primary outcome was HIV infection and the secondary outcome was incidence of HSV-2 genital ulcers.

The researchers found that the incidence of HIV was 3.9 per 100 person-years in the acyclovir group compared to 3.3 per 100 person-years in the placebo group. The hazard ratio was 1.16, with a 95% confidence interval from 0.83 to 1.62.

So despite a 47% reduction in the incidence of genital ulcers in the acyclovir group and a high reported adherence to the study drugs, there appeared to be no change in the incidence of HIV.

What does that mean for patients? What should you tell patients who are HIV negative but HSV-2 seropositive about using acyclovir to reduce the risk of HIV?

I would explain that although, based on previous studies, herpes infection appears to increase the risk of HIV,^20,21 recent studies have not found a benefit of herpes treatment in terms of preventing HIV infection.

I would discuss the very real potential of enhanced HIV transmission with herpes infection through macroscopic or microscopic ulcerations or through an increase in activated T cells in the genital tract. I would emphasize the use of known interventions, such as regular condom use, to reduce possible HIV transmission.

Pre-Exposure Prophylaxis (PrEP)

As I mentioned, other opportunities for HIV prevention occur before and after HIV exposure through the use of vaccines, microbicides, pre-exposure prophylaxis or post-exposure prophylaxis.

One area that seems to have the greatest potential is the use of antiretroviral agents for prevention, or pre-exposure prophylaxis, also known as PrEP.

The use of pre-exposure prophylaxis is supported by the success of using antiretrovirals to prevent mother-to-child transmission,²⁴ and also by the many case studies of post-exposure prophylaxis²⁵ and the experimental studies in macaques.^26,27

In addition, available antiretrovirals are safe and can be administered once a day, which would obviously facilitate their use in this manner.

There has been some interesting work done at the CDC on pre-exposure prophylaxis. An animal model was developed in which macaques that were exposed to HIV rectally all become infected.²⁸ But in macaques that were given antiviral drugs such as tenofovir [TDF, Viread] and FTC [emtricitabine, Emtriva] before exposure, the rates of infection were found to be reduced. In fact, a combination of FTC and tenofovir appeared to be the most effective pre-exposure prophylaxis for reducing HIV transmission.

Unfortunately, the one completed pre-exposure prophylaxis study, which was conducted by Family Health International, failed to show that once-daily tenofovir, given orally, was efficacious in preventing HIV transmission.²⁹ This was a phase 2 trial in women from Ghana, Cameroon and Nigeria who were at risk for HIV. They were given tenofovir or placebo. There was inadequate power to assess the efficacy of tenofovir due to an inability to recruit the expected number of women into the study.

Currently, there are several trials assessing the efficacy of pre-exposure prophylaxis that use tenofovir or tenofovir and FTC. They included the Tenofovir Extended Safety Study (CDC), the Bangkok Tenofovir Study (CDC), the Botswana TDF2 (TDF/FTC) Trial (CDC), iPrEX (UCSF/NIAID/BMGF and Partners PrEP).

Some are multi-site international studies, but most are taking place exclusively in Africa. The results of the first of these studies should be available in 2009.

An enormous number of people -- more than 19,800 -- will be participating in the seven pre-exposure prophylaxis studies that are either in progress or planned. The studies will include participants with diverse experiences and risk factors for HIV and will include heterosexual women (11,050), heterosexual men (2,950), MSM (3,400) and injection drug users (2,400). This should probably provide the best evidence yet of whether pre-exposure prophylaxis is efficacious in preventing HIV transmission.

Although pre-exposure prophylaxis has shown efficacy in reducing HIV transmission among macaques, there has not yet been a human clinical trial showing reduced transmission.

It has been stated that some people, especially gay men, may be using pre-exposure prophylaxis before engaging in high-risk sexual activity; however, this has not been confirmed.

Issues that still need to be addressed include the effects of pre-exposure prophylaxis on HIV drug resistance. It is also important to know what the effect of taking PrEP will be on behavior; for example, are people going to use pre-exposure prophylaxis instead of other known and effective preventions such as condoms? Other issues such as the cost and access to PrEP are very important and need to be considered as well.

Medical providers who may be approached by patients for pre-exposure prophylaxis need to remember that it is not currently the standard of care to provide pre-exposure prophylaxis to patients outside of a clinical trial setting. We will soon have definitive results on efficacy available from the many studies in progress.

Treatment as Prevention

Another prevention strategy that has been discussed a lot recently is reducing the transmission potential of HIV-infected persons through HIV treatment.

Important questions that need to be asked are whether the person on antiretrovirals is less infectious, and the degree to which transmission is still possible.

There are retrospective studies of couples that suggest when you treat the infected person, his or her partner is less likely to get infected.^30,31 There are also observational studies that confirm this.³²

Reduced transmission potential can be demonstrated through studies that examine the amount of HIV detected in genital secretions, which has been found to be lower when patients are receiving antiretroviral treatment.^33,34

The statement by the Swiss Federal Commission created a lot of controversy.² In their letter to other physicians in Switzerland, the Swiss Federal Commission stated that "HIV-positive individuals without additional sexually transmitted diseases and on effective antiretroviral therapy are sexually non-infectious." This caused a lot of controversy in the rest of the world.

The Swiss guidelines note that the risk of HIV transmission during sex without a condom is less than 1 in 100,000 under very strict circumstances. The specific circumstances are in the case of an HIV-infected individual who is fully compliant with antiretroviral therapy, evaluated regularly by the treating physician and the viral load must have been undetectable for at least six months. The Swiss only looked at this in monogamous, heterosexual settings where no other sexually transmitted infections were present.

To evaluate the Swiss guidelines, Suzanna Attia et al from the University of Bern reviewed the sexual transmissibility of HIV according to viral load, HAART [highly active antiretroviral therapy] and sexually transmitted infections.³⁵ Her presentation was entitled "Can Unsafe Sex Be Safe?"

The presented research was a meta-analysis that was conducted to estimate the risk of HIV transmission among serodiscordant couples.

Out of 252 published articles and abstracts investigating HIV transmission, only 14 studies were found to be eligible for inclusion in the investigators' meta-analysis. Actually, no studies fulfilled the exact criteria of the Swiss statement, such as being free of sexually transmitted infections or having an undetectable viral load for six months.

In the meta-analysis, most of the studies were in serodiscordant heterosexual couples. The researchers included 14 cohorts identified from 165 published articles and 93 abstracts reporting on 5,161 heterosexual serodiscordant couples with 433 HIV-infected partners who were receiving HAART.

In four of the papers and one of the abstracts, with a total of 1,587 untreated HIV-positive partners, no transmissions were reported from those individuals with a viral load of less than 1,000 copies/mL.

Only eight studies had detailed information on antiretroviral therapy, and only seven had information on concurrent STIs [sexually transmitted infections]. As you can see from these data, information on antiretroviral therapy was missing in many studies, as was information on concurrent sexually transmitted infections.

No studies in the meta-analysis completely fulfilled the Swiss criteria. One transmission did occur in a patient who had a viral load of less than 400 copies/mL, although it was stated that this patient was not receiving antiretroviral therapy at the time.

What are we to make of the Swiss guidelines, and how relevant are they to the majority of patients we see in our practice? Attia et al wrote in their abstract, "This meta-analysis and an ongoing multi-centre, randomized trial will provide more precise data about HIV transmission risk under HAART. At present, the negative impact of a public message that has been interpreted as promoting unprotected sex might outweigh the potential benefit to the intended recipients."

Many patients in my clinic were extremely excited about the possibility of sex without the need for condoms. I work in an urban health center that predominantly serves gay and bisexual men. My conversation with patients usually involves warning them that although there have been no reports of HIV transmission occurring from individuals with an HIV RNA of less than 40 copies/mL, the studies that have been conducted predominantly involve heterosexual couples and there are no data existing for anal sex.

Patients also need to be aware that occasional spikes in viral load may occur even in individuals who are adherent to antiretroviral therapy.³⁶ In addition, unprotected sex puts them at risk for other sexually transmitted infections, many of which are asymptomatic, and may increase the likelihood of transmitting or contracting HIV.

I think it is fair to state that a patient with an undetectable viral load on antiretroviral therapy has a much lower risk of transmitting HIV; however, this is a big step from guaranteeing absolutely no transmission risk. My recommendation remains that all patients continue to use condoms with their serodiscordant sexual partners.

Should HIV Superinfection Be a Concern?

The last point I would like to discuss related to unprotected sex is whether it is safe for seroconcordant HIV-positive people to have sex without condoms.

Serosorting has been used with variable success as a method of reducing HIV transmission, but do the risks include HIV superinfection? The risk of superinfection was investigated in the Positive Partners study, a prospective study of HIV-positive, seroconcordant sexual partnerships in San Francisco.³⁷ Three hundred ninety participants were recruited, and 329 were eligible due to the availability of baseline viral sequencing data. Viral sequencing was also conducted at the end of the study at follow-up.

In this study:

• The mean length of time of positive HIV status was 9.9 years.
• Two hundred eighty-seven participants (87%) were infected for more than one year prior to enrollment; 146 (44.4%) had been HIV positive for over 10 years.
• On average, participants had 77 episodes of unprotected intercourse per year.

There were 233 infected individuals followed prospectively during a total of 221 person-years, and at the end there was no evidence of superinfection occurring among participants.

Using the author's model, 24 superinfections were expected after adjusting for viral load and antiretroviral use if superinfection occurred as efficiently as primary HIV infection, but again, this did not occur.

Superinfection appears to be rare in patients who have chronic HIV infection, but it may not be as rare in patients with recent HIV infection.

The mechanisms blocking superinfection may include viral interference, antiviral immune responses, or antiretroviral effects.

It is important to remember that the transmission of STDs can still occur; we need to be mindful of viral hepatitis, especially B and C, and HPV [human papillomavirus] transmission.

Patients thus need to be fully aware of the other non-HIV risks if they are contemplating unprotected sex within their seroconcordant relationship.

Summary

To summarize all of the points I have covered:

HIV incidence is higher than previously expected, using new technology developed by the CDC.¹

The burden of disease is higher among certain groups, such as men who have sex with men of all races, African Americans and Hispanic Americans. This means that we need to appropriately target prevention efforts in these communities.

As well as behavioral and structural efforts, there are exciting efforts underway to reduce HIV transmission through the use of antiretroviral therapy both as pre-exposure prophylaxis and post-exposure prophylaxis.

With regard to STI treatment and HIV, unfortunately, the use of antiviral treatment for the suppression of herpes simplex did not appear to have an effect in reducing HIV transmission in two large randomized controlled trials that were presented at AIDS 2008.^22,23

Whether HIV-positive patients on effective antiretroviral treatment can forgo condoms has been a subject of much debate and more research is needed in this area.

Lastly, there appears to be no increased risk of HIV superinfection among seroconcordant HIV-positive couples with long-term infections.

It is clear that we have a long way to go with prevention efforts. It is unlikely that the solution will be found in any one strategy, but will need to be a combined approach of behavioral, structural and bio-medical interventions.

This transcript has been lightly edited for clarity.

References

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