Spotlight Center on HIV Prevention Today

HIV Prevention 2007: A Guide for Health Care Providers

Translating HIV Research Into Practice

December 12, 2007

Table of Contents


Moderator: Welcome to HIV Prevention 2007: A Guide for Health Care Providers. I would now like to turn the conference over to your speaker, Dr. Thomas Quinn.

Dr. Quinn: Thank you very much. Good afternoon or good evening to all of you. I'm going to be talking about changes that we have witnessed in a number of aspects of HIV prevention over the past year, hence the title, HIV Prevention 2007. This has actually been a year in which we can reflect about some successes and some failures in our ability to slow the HIV/AIDS epidemic, something that we should all be cognizant of and should all practice in dealing with our patients on a day-to-day basis.

You will notice that I will highlight a fair amount of international or global HIV epidemiology, and that is partially because of the focus of where most HIV cases occur. But some of you may be aware that just today there have been several press releases about an increase in the number of HIV cases that have occurred over the past year here in the United States. And so wherever possible, I am also going to refer to our national theme as well.

Number of People Living With HIV; New Cases

If you can see these slides, and I hope you can, this next graphic basically shows the spread of the epidemic escalating over time up to all areas of the world. There is not a country without HIV/AIDS at this point, 26 years after recognition of the first case of AIDS. And you can see that it has continued to escalate every single year; there has been a dramatic increase.

This year, especially just last month on World AIDS Day, beginning of Dec. 1, UNAIDS and WHO did a correction in the numbers of cases. They actually downgraded the number from 39 million people living with HIV to approximately 32 million people with AIDS, but it has a wide confidence interval. Now I want to mention -- this is very important -- because a lot of individuals have thought, oh it's going down, therefore, prevention is working, and we're making progress. Basically UNAIDS made an adjustment in the number of cases infected due to better surveillance and, retrospectively, they have also decreased the previous numbers. So this is an inexact science as to how many people are living with AIDS. We don't even know how many people are living in the world. So it's even more difficult to try and estimate the true exact number of people that are currently infected with HIV. The fact remains though, if you look at these statistics, that over 30 million have been infected [and another] 30 million have died, giving us a total number of 60 million who have been infected with HIV since the beginning of the epidemic; 33 million or 38 million, it doesn't really matter, it's a large number of people that have become infected over the years and are living, and many needing HIV care at the present time.

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Now, in the middle of the graphic, you can see I put in a percentile; that is the estimated prevalence of HIV throughout the entire African continent. However, in the darker red countries, rates of 15% - 34% of HIV may actually occur in those populations. But when you divide all of the HIV infections by the entire population of the continent of Africa, which is about 500 million people, you work out to an estimate of 5%. There is no doubt Africa, particularly the southern cone of Africa, has really borne the greatest burden of HIV infection throughout the world. Before I leave the slide, focusing on the 5%, you should be aware that the District of Columbia, our nation's capital, actually has the same prevalence rate. It is not that much different than what we are witnessing in Africa, compared to what we're witnessing in our nation's own capital. HIV is definitely increasing and devastating many peoples' lives throughout the world.

This particular graphic -- which is also from UNAIDS and which I've modified just slightly graphically, but the data are the same -- basically gives you a feeling about how many people are becoming newly infected with HIV. It sort of gives us a better estimate of how we really are doing in prevention. And as you can see, during the course of 2007, 2.5 million people became newly infected. This is despite 26 years of recognition of this disease and knowing how it spreads; we have failed to slow it dramatically enough to lower these types of estimates. It works out that every 10 seconds, a new person is becoming infected; 2.1 million people died from HIV this past year (2007). So if you look at these two numbers (2.5 became newly infected, 2.1 died), we're basically at an equilibrium and the numbers of cases will continue to increase because of treatment and I would project that these numbers of HIV-infected people living with HIV will go up. What prevention is supposed to do is prevent these 2.5 million new infections.

Here is where the challenge really remains. We just have not enabled our societies well enough to be able to slow the epidemic. I put in the graphic an idea of how many new infections occurred in each of the regions. If you look at Africa, of the 2.5 million new infections worldwide, 1.7 of those occurred in Africa. That's two-thirds of all the new infections that are still occurring in Africa. South and Southeast Asia come next, followed by Eastern Europe, and then, of course, Latin America. If we go to North America, predominantly the United States, this number (46,000) of new infections is actually going to be changed over the next several weeks. Estimates from the CDC are now suggesting that this number is actually going up; the exact number, I don't know yet. But if you follow the press, you will probably see how that will develop over the next several months.

Impact on Life Expectancy, TB Rates

When Africa has such a terrible epidemic, it obviously is impacting the lives of all those people in Africa. This particular graphic I always show because it underpins the tragedy of HIV/AIDS. And if you look back in 1970 up to 1990, the life expectancy in some of these African countries was increasing, as high as in the mid 60s years of age. Then with the epidemic of HIV, you can see about 20 - 30 years of life expectancy have been lost. This is truly a dramatic change. No other disease over this span of years has ever accomplished this same type of reversal in life survival and life expectancy. So it really does give us pause and a challenge as to how to reverse this tide of the epidemic. Now HIV in itself is a fatal disease, but it's also impacting other opportunistic infections.

And this particular graphic actually looks at TB (tuberculosis) incidence in 1990, and then compares it to 16 years later. If you go by the color-coding, it gives you an idea of the impact per 100,000 population within these regions of the world. Most of them remain color stable. They didn't really change very much, except for one area, and that's the continent of Africa, and it's all due to HIV. HIV is increasing the clinical diagnosis and morbidity and mortality due to tuberculosis. The other fact to keep in mind when we talk about TB is how in many of these cases, multiple-drug-resistant TB and extreme drug-resistant TB are rapidly occurring in many areas of Africa and other areas of the world. It is particularly bad in Africa because it's exacerbated by HIV, making these people more infectious.

Let me just quickly summarize the current status of the HIV pandemic. Especially in Africa, it has reversed development gains of three decades. It has caused an economic decline. It has thrown health systems into absolute chaos. It has resulted in political instability and security concerns, increasing numbers of orphans due to the premature death of their parents. All of these factors leading to an immense humanitarian outcry to try and provide relief, particularly to the continent of Africa, where the AIDS epidemic has been so bad.

Prevention: Behavioral Change

So now let's go to prevention. If that is what the epidemic is, how do we go about changing the course of the epidemic? And right now the main way to prevent new infection is to actually focus on both biomedical and behavioral change. For the first 20 years of this epidemic, we have totally focused on behavioral change. That behavioral change includes voluntary counseling and testing, education and behavioral modification, drug abuse treatment and needle exchange programs. In some areas, these have been successful, and we are seeing some reversal in the AIDS epidemic, as I'll show you shortly. In other areas, it has totally failed. Unfortunately the last bullet here, abstinence, be faithful and condoms -- the ABC approach to HIV prevention by sexual transmission -- has been politicized a little too much. The abstinence is important, but it needs to be focused in on young individuals before they start sex. Once they start sex, then it's being faithful or utilizing condoms to protect their partners, as well as themselves, from subsequent infections. Hopefully in the future, this will be less politicized, but still incorporated in prevention messages that we give to individuals to protect themselves from HIV.

Now I mentioned that those types of behavioral interventions have worked in several areas. This is just a snapshot, this next slide, looking at Kenya, several cities within Kenya, showing that when HIV was starting to increase in the perinatal population between 1997 and 2000, these types of prevention programs on behavioral change were implemented, and you can see that there was a decline and then a subsequent stabilization. This has been repeated in many other countries. Thailand is another huge success story. It probably did work for the United States for awhile, especially in the late 1980s and early 1990s, but after about 1995, we reached the stabilization stage. We have almost every year, [and] for the last year, had an estimate of anywhere from 40,000 to 60,000 newly infected people, and that is where we have not been able to change the course of the epidemic.

Prevention: Biomedical Intervention

Perinatal Transmission

So there has been a renewed emphasis on biomedical interventions. And perhaps the greatest success in biomedical prevention of transmission of HIV has been from mother to infant. The next graphic shows that success. And most of you are probably with this CDC graphic showing the number of cases reported to the CDC across the 50 states of children who have become infected from their mothers through perinatal transmission from 1985 through 2004; 2005 and 2006 [have] even lower numbers. But you can see it was steadily increasing, and then with the advent of AZT therapy during pregnancy and subsequently with combination therapy during pregnancy, we have seen a marked decline in transmission of HIV from mother to infant.

While this was a great success and has almost eliminated mother-to-infant transmission in the developed world, it took many years for this type of advance to move into the developing countries of the world where HIV perinatal transmission occurs much more commonly. But ultimately it did with cheaper antiretroviral drugs that could be utilized, like nevirapine. And this shows on the red line the decline in percent transmission from mother to infant going from 25% down to less than 1% through the use of antiretroviral drugs and, about 5 to 8 years later, we start to achieve the same success rate in Thailand and in countries in Africa, all now ranging about a 1% to 4% transmission rate. We can do better, and we need to strive to do better.

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At the Sydney conference this summer -- and this was probably one of the greatest reports at the conference that I heard -- there was a report out of Rwanda, and it was called the AMATA trial. And in that trial, HIV-infected women who were counseled and tested, but were pregnant, were enrolled and offered antiretroviral drugs independent of their CD4 to try and block HIV transmission. The mothers were allowed to choose whether they would formula-feed their infants or exclusively breastfeed their children. If they chose formula feeding, the antiretroviral drugs were continued for one month after delivery. If they choose to breastfeed, they were continued throughout the breastfeeding period and stopped one month after the baby was weaned from breastfeeding. They then looked at transmission rates and overall, for the entire population, it was 1.6%; there was only one child infected postnatally through breastfeeding, and that's because the mother had stopped her medications and viral load had rebounded.

What I found fascinating in this study was that the cost of six months of generic antiretroviral drugs while the mothers were breastfeeding was actually slightly lower than the retail cost of six months of formula. So for those individuals who said antiretroviral drugs are too expensive, you can't give them during breastfeeding, this particular study proved that wrong. It is an adjunctive method to biomedical prevention of HIV transmission. Now pregnant women in the United States are still recommended not to breastfeed; however, should they really insist on breastfeeding, they should be continued on antiretroviral drugs during the breastfeeding period so as to avoid transmission.

So perinatal transmission [prevention is a] great success, now being rolled out throughout all areas of the world, but there is one downside, and that downside has been how to scale this up to remote rural areas of Africa. This just basically shows that we are increasing antiretroviral therapy to adults. From 2003 - 2005, this graphic shows it went from 7% to 20%. It is now up to 30%. Now access of mothers to child prevention services, that is all pregnant women being screened and given drug, only went from 7% to 9% in the same time period. Clearly, very different from treating our HIV-infected population. The percentage of infected mothers who actually received antiretroviral prophylaxis was still <10% in 2005. So I would say on one side researchers, clinical practice, huge success on prevention of mother-to-child transmission. In terms of translating that to policy and then scaling it up throughout the entire population, it has not met expectations, and we have a long way to go.

Reducing Sexual Transmission: ARV Therapy

So let me move now to sexual transmission. Perinatal transmission is very straightforward and simple to follow, but sexual transmission is much more complicated. It's complicated because there are a number of variables which influence infectiousness of an infected individual and a number of variables that affect susceptibility of the uninfected partner. So if you're going to design an intervention, somewhere here or here, obviously there are other factors that need to be controlled for or modified to some degree. We will keep these variables in mind as we go through the next series of slides.

A reason I got involved in this study has been to look at discordant couples where one person is infected and one is uninfected. And we found that as the viral load goes up in one individual, the infected individual or index case, transmission to the partner goes up equally, whether it's male to female or female to male. And they're fairly similar with a few exceptions, which I'll talk about. Like perinatal transmission, if with therapy you can change this dynamic to get these people to undetectable viral loads, you theoretically should be able to block transmission. So just like mother-to-infant transmission, we might be able to achieve some success in decreasing sexual transmission if the individual gets put on therapy.

There is actually data on this. And this was also presented at the International AIDS Conference, which was held in Toronto a summer ago. Let me just summarize it. One thousand serodiscordant couples were followed in Rwanda. Of those serodiscordant couples, about 250 were "index cases" that had CD4s <200, and so they got started on antiretroviral therapy. In spite of the counseling of the 1,000 serodiscordant couples, 42 seroconversions did occur, but only 2 of those 42 seroconversions occurred when the partner was on antiretroviral drugs. If you translate this statistically, then therapy with antiretroviral drugs leads to an 80% reduction in HIV transmission when following discordant couples, which was highly statistically significant. So this works and is another huge success, I think in terms of blocking transmission.

We'll come back to this because you obviously, once infected, don't want to immediately go on antiretroviral drugs. You're most infectious during the acute period, and that's the period when you're not on antiretroviral drugs. So therapy late in the disease will not affect all transmissions, but it will affect late transmissions, if you will.

Let me just skip for a second and talk about the international response to the AIDS epidemic, and that's shown here. We went from almost negligible donations up to $10 billion/year being donated for the care of HIV-infected people throughout the world. The impact of that is starting to be felt in countries like Botswana, and this shows that mortality is declining in a hard-hit country like Botswana, as the percentage of people being placed on antiretroviral drugs increases. So this is a great success record, and it probably will affect sexual transmission that occurs late in the course of infection.

Reducing Sexual Transmission: Male Circumcision

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Let me jump to the biggest success of 2007 in HIV prevention/biomedical aspects of prevention -- and that is the effect of circumcision in young men in decreasing acquisition of HIV. I'll skim along some of this because you probably have read plenty about it. There were three circumcision trials that were done in Africa. All were stopped prematurely by their Data and Safety Monitoring Boards (DSMBs) because of proven efficacy. The efficacy is shown here; a lot of numbers on this slide. I circled the ones that are important. If you look at the South African trial, Ugandan trial, or Kenyan trial, and you go down to percent protection, you find numbers that are almost identical -- 51% to 60% if you do an intent-to-treat analysis. If you do an as treated analysis, it's actually slightly higher: 60% to 76%. Remarkable uniformity among these three trials, and that's why the DSMBs -- and there were two separate ones -- stopped the trials and said you need to circumcise the control arm.

This graphic actually shows the results of the three trials with their confidence intervals showing decreased odds ratio in circumcised individuals for acquisition of HIV, and these last two are all of the meta-analyses of all the published epidemiologic studies. You can see once again tremendous uniformity. There is no one that doubts these data that circumcision will provide some, not 100%, but some efficacy or protection against HIV acquisition among heterosexual men.

Now the burning question is what about men who have sex with men, and we really don't have any data. There have been no studies, i.e., randomized trials, done in gay men to determine whether circumcision would be protective in that population or not. But certainly in heterosexual men, this type of effect definitely decreases acquisition, and if it decreases acquisition in a man, it will decrease transmission to the female if the man is not infected.

I'll just show you a few other pieces of the data. This is from the Ugandan study. The protective effect of circumcision shown in the red bars actually increases from the time of surgery. So once you're two years out from the surgery, you actually have 75% protective efficacy. If this was a vaccine against HIV with this type of efficacy, we'd be dancing in the streets. This would be the home run, the grand slam, that everyone has been looking for. We don't interpret it quite that way because this is a surgical procedure, it's aimed at heterosexual men predominantly, and all three studies were done in Africa, so the results have been "generalizable" to Africa. Outside Africa, outside of heterosexual men, it is not entirely clear what that protective effect will be. It also is effective (shown in the red bars are the circumcised men compared to the uncircumcised men) throughout all of the age groups, from 15 years of age out to 49 years of age. And one of the beneficial side effects of circumcision, besides decreasing HIV acquisition, has been decreased acquisition of genital ulcer disease. It actually reduced it by 50% in the Ugandan trial, the South African trial, and in the Kenyan trial. It has no effect on gonorrhea or chlamydia because those are urethral pathogens.

The Kisumu trial, which is the Kenyan trial, here is their decline in genital ulcer disease. Discharge really did not change much. But interestingly, they found a decline in HPV causes of warts, and that has been described in the past as well, that circumcised men have lower rates of HPV and genital warts and consequently, their female partners have less cervical cancer.

So how does this work? What's the biological methodology that causes this to happen? It turns out, in circumcise, what you're doing is you're removing the foreskin. And if you look under a microscope, that foreskin is loaded with HIV target cells, Langerhans cells, CD1a positive, antibody positive cells. That is shown in this particular graphic, in these red cells (dendritic cells) in the foreskin of a circumcised man that has been examined under special staining. And this is the low power, showing that these are widely abundant throughout the foreskin. So when you remove the foreskin, you are removing those target cells.

All of this came together at the beginning of 2007. UNAIDS and WHO fully endorsed it, and I want you to be aware of the recommendations. And that is that male circumcisions should now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men. Again, the caution, we don't know whether this would work among men who have sex with men. So we actually think from modeling studies, this could have a tremendous effect. The issue is: How do we scale it up to actually achieve that great success?

Reducing Sexual Transmission: Suppress Genital Herpes

The other area in prevention that there has been a lot of attention has been if we could affect genital herpes, suppress it, treat it, we might be able to reduce HIV acquisition and HIV transmission. This diagram shows that these two viruses work in concert together to increase susceptibility in infectivity of both HIV as well as herpes. If the person is dually infected, it increases the frequency and duration of herpetic ulcers. One particular study actually showed -- and this is in press in AIDS -- that nearly 45% of all new infections in Uganda, and 67% of new infections in Zimbabwe, may be attributable to having both prevalent and incident genital herpes. So if we could suppress herpes with valacyclovir or acyclovir, generically, we might be able to change the dynamics of HIV.

Several studies have been done. One was recently published this year in New England Journal of Medicine, which came from Burkina Faso. It was a French study in which they randomized women who were dually infected to HAART or not being on HAART, and half of them received valacyclovir and the other half did not. In the arm that got the valacyclovir, there were marked decreases in genital HIV RNA quantity and plasma HIV RNA -- half a log decline. Valacyclovir has absolutely no effect on HIV in vitro. So this effective decreasing of the viral load of HIV by giving valacyclovir is a direct effect of the suppression of herpes. These studies are going forward.

At CROI this year, we hope to be hearing about a major study in which acyclovir was used to decrease HIV acquisition in people who were already herpes-infected. but at risk for HIV. [Investigators] are also doing studies throughout Africa to actually see if valacyclovir or acyclovir given to dually infected people will decrease transmission. The results of that won't be in for a year. But if these succeed in Africa, there is absolutely no reason why they won't work in the United States as well, where dually infected people do exist in fairly large numbers.

Reducing Sexual Transmission: Female-Controlled Methods

We have talked about circumcision and herpes and antiretroviral drugs. When you talk about prevention, we have to focus on female methods of protection and how women can try to protect themselves, because they are less empowered in most sexual relationships in convincing their male partners to use condoms or to allow them to use female condoms. Abstinence, which everyone professes, or being faithful, is unlikely to protect married women or those who are sexually abused. So they clearly need steps to protect themselves. Unfortunately, 2007 was not a good year for coming up with positive results in the prevention field to help women protect themselves.

The first study that got published was that of Nancy Padian, which was done in sub-Saharan Africa. This looked at comparing the use of a diaphragm and lubricant gel versus the same type of education, condom distribution, and so forth. Condoms could be used as well in the intervention arm. But what you see here, and this was published in Lancet, is that it had absolutely no effect. The diaphragm does not preferentially protect against HIV acquisition. So this was hoped to provide women with some means of protecting themselves, but it obviously failed.

There have been microbicide studies that have also been conducted over the years to try and help women protect themselves. The first set using nonoxynol-9 failed. In fact, it enhanced transmission. A number of other candidates are being evaluated, and one that was presented in Sydney is cellulose sulfate. The DSMB stopped the study prematurely because of increased infection in the women using the microbicide. So it's the absolute reverse of the effect that was anticipated.

This shows the Kaplan-Meier curve. Here is the cellulose sulfate arm showing increased numbers of infections of HIV compared to the placebo arm. It is clear from these data that no matter how you analyze it, more people got infected using the microbicide than those using the placebo. So the diaphragm didn't work, the microbicide didn't work. We're sort of back to the drawing board as to which microbicide might be the most efficacious in blocking acquisition of HIV in women exposed to infected men.

So the year is going to close out probably on one of the most disappointing variables seen in the HIV prevention field, and that's the HIV vaccine field. We still, after 26 years, or if you really want to be accurate, 23 years of knowing about HIV, we still don't have a vaccine. The ultimate goal of a recent vaccine trial was to try and lower viral load by inducing an immune response to HIV that would limit its replication in vivo. It wasn't meant to really block infection, but it was meant to modify the infection and prolong survival as a result of the vaccination arm.

Unfortunately, it didn't fold out that way, and most of you have seen this in the news as well. I thought I would summarize it for you. This was a Merck vaccine that was done in collaboration with the HIV vaccine trials network, led by Larry Corey. It's an adenovirus vector that encodes for HIV GAG/POL/NEF. The DSMB monitoring the Merck study of this vaccine called a halt to the study about 13 months post-vaccination. Of 3,000 volunteers enrolled, 49 of the vaccine recipients became infected compared to only 33 in the placebo arm.

This is somewhat similar to the results of the cellulose sulfate study; that is, the intervention seemed to do worse than the control arm. And when they carefully analyzed it, it turns out that the people who got increased infection in the vaccine arm were those who had antibody to the adenovirus compared to the placebo arm. So just focusing on antibody positive individuals to adenovirus, the vector in the vaccine, 29 became infected versus 13, which was statistically significant. Now you recall I said that the main aim of the vaccine was obviously not to increase infection; it was to at least have equal rates of infections in both arms, but to lower viral set point. Unfortunately, it didn't do that either. Both arms had equal viral load set points.

Reducing Sexual Transmission: Summary

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Let me summarize for 2007. There have been 33 randomized control trials published in which HIV is the outcome. Some of these have included behavioral change, circumcision, diaphragms, microbicides, pre-exposure prophylaxis, STD treatment and the vaccine trials. Of those 33, only 4 have succeeded. So the biomedical approach to blocking HIV sexually -- and I'm just focusing on sexual transmission -- has been a tough up road battle. Three have succeeded in the circumcision. The one here that is still underway -- it's actually not completed, they're still following the individuals -- this is a circumcision trial of HIV-infected people to block transmission of HIV. And there was an STD trial that succeeded in Rwanda/Tanzania.

So if we look at our armamentarium to block HIV transmission biomedically, male circumcision works for heterosexual men; we don't know about men who have sex with men. The others have essentially failed or are being followed. Some are still underway. And you can see there are a number of other studies still planned, but the vaccine move has literally been derailed.

I'm going to take you back to the very first set of slides, and that is the first approach to prevention has been a behavioral intervention for sexual transmission. Perinatal transmission, very clear, easy to do. I didn't focus on injecting drug use, but certainly the needle exchange programs have been a huge success. They have not been endorsed fully by this country. It poses a problem in terms of needle exchange programs, if the state doesn't allow it. But for sexual transmission, which makes up 80% of all transmission, we have a ways to go for a better success record.


Let me just summarize the lessons learned for this past few years and the future challenges, and that is biomedical interventions, like prevention of mother-to-child transmission, STD treatment, especially of genital ulcer disease and I hope to of herpes, and circumcision do, in fact, work, but they need to be scaled-up to maximize HIV control. I actually think antiretroviral drugs can be implemented throughout the world, and that they will impact transmission to some degree, not 100%, but some. Where the challenges are is coming up with better microbicides to help women, pre-exposure prophylaxis for both men and women, and obviously better vaccine research going forward to have a better prevention effect.

Half of Projected New Infections Could Be Prevented

The last comment I want to make is that of the next 60 million [HIV] infections projected to occur, over the next seven to eight years half of them could be averted with comprehensive scale-up of these proven prevention strategies integrated with effective care programs.

Thank you for your attention. I see there are some questions. I'd be glad to start going over them.

Questions & Answers

Dr. Quinn: The first one that is on my screen says: If you have an HIV-infected person in the developed world who really wants to breastfeed -- so a woman here in Baltimore or Seattle or wherever -- what would be the risk now that we know what we know, and what sort of guidelines should we give someone like this?

I'll be very direct about this, because it's my bias, I guess. The CDC guidelines do recommend that we should counsel women against breastfeeding because the virus can be transmitted in breast milk. It is absolutely well known, and you should definitely give that advice to the woman right upfront. Now, if she still says she is going to breastfeed, despite what you've told her, then I would continue at least a two- or three-drug regimen independent of her viral load or CD4 -- that doesn't factor into this. If she is going to breastfeed, she needs to have an undetectable viral load. She needs to be on the best regimen you can give her while she is breastfeeding. That's probably six months to nine months worth of treatment, and I would strongly recommend that if you know that she has an undetectable viral load as result of that regimen.

So basically you give her two recommendations; she should not breastfeed, but if she really insists, then she must maintain antiretroviral drug treatment while she is breastfeeding and she must have an undetectable viral load. She needs to know that there is a risk by breastfeeding which is greater than not breastfeeding. So I hope that answers that question.

The next question is: Based on what we know about possible transmission of HIV when someone has an undetectable viral load, would you then say that [persons] who have never had a detectable viral load in more than 15 years can safely have unprotected sex?

I will never say that. There is always a risk. It is very, very small. The likelihood they're going to transmit HIV is so profoundly low, it's hard to even quantify it, but is it absolutely zero? No. Remember, even though detectable viral load is being measured as free virus in the plasma or in the semen, wherever you're looking, there is still viral RNA/DNA integrated into cells in the latent reservoir of these individuals and that could be inadvertently transmitted. There are cells in semen, and so there is going to be a risk that once that virus enters into someone else's body, it might actually start to replicate due to the change in the environment of the cell. That's all hypothesis. I can't give you a very definitive answer other than to say if you were playing the probability game, it's probably 1 out of a million that transmission will occur -- 1 out of a million sex acts -- but would you want to take that chance or that risk with a loved one? Only the patient can answer that question.

So the next question I have is: I didn't mention the University of North Carolina studies regarding nucleic acid amplification to detect HIV infection during one of the most infectious periods of acute HIV.

Thank you very much for bringing that point up. I did mention acute HIV is the infectious period of an individual's lifelong infection with HIV. About 43% of all transmissions actually occur during this acute period in which they have unprotected sex with a partner and transmission occurs. Now what the questioner is posing is that the University of North Carolina and the state of North Carolina actually did blood bank screening through pooling of blood to look for acute HIV, and actually they found a fair number and then were able to counsel those individuals and to hopefully avert transmission.

What's the practicality of that? Actually, I think in the developed world, highly practical. That, in fact, we should be looking for acute HIV as often as possible and with cost effective means, which we now have. Can this be done in Africa? Well again, blood donation doesn't work quite the same way. They did do it in STD clinics and other high-risk populations. I work in Uganda; there are not many STD clinics there. There are just general clinics that people go to. [The possibility] to be able to identify it in some of those settings is still very low. I have looked very hard for it in emergency departments here in the U.S., and while we can find it, it is still of low probability. Does that mean we shouldn't look? No, we should definitely be trying to look at identifying these people, get them counseled and hopefully avert transmission.

I'm going to move to the next question. Are you a proponent of the CDC recommendations for universal HIV testing?

We first pioneered this actually in Uganda about five or six years ago in a hospital called Milago Hospital across from McCary University. They actually did routine HIV testing with opt out. That is, everyone gets tested, but if you don't want to, you can say, "No, I don't want to be tested." And we actually found extremely high rates of infection, and we immediately referred those individuals across from the hospital to an HIV care clinic, called the Infectious Disease Institute.

So am I a proponent of it? I actually am. I actually think it would be absolutely critical for people to be tested and to know whether they're infected or not. They can get into care earlier. They can be educated about the prevention of transmission. Most people and most counselors and clinicians are not going to spend the hour or more [to talk] to people about HIV, so therefore I strongly support it.

Let me keep moving on here to the next question: I've heard the phrase, "HIV treatment is HIV prevention." Is this all about getting viral loads undetectable?

I'd like to say that's what it is, but it's a little bit more complicated. It does turn out that in individuals who get put on treatment, the goal is to get their viral loads undetectable to make them less susceptible to the immunosuppressive phase of HIV. At the same time, it brings them into care where you can educate them about prevention. So it has two purposes; one is the educational purpose, and the other is actually to get their viral loads undetectable, in which case they will be less infectious. Absolutely. So just remember both fit into that category.

So next question is: What do you make of the recent [study] conducted by Millet of the CDC who found no association between circumcision and HIV status among black or Latino, bisexual or homosexual men? Why would you think there would be no protective effect for those men?

Obviously, if a man engages in anal rectal sex and is the receptive partner, whether they're circumcised or not, is going to have no effect. And if the study very carefully teases out -- and one study did -- whether they are predominantly 100% insertive versus insertive and receptive versus receptive, circumcision was only protective in those men who were only insertive in their sexual practice. So I wasn't surprised by that at all. It all comes down to what is the type of sex you're having, insertive versus receptive and whether circumcision in gay men or bisexual men still needs to be evaluated.

The last question I think here is: Do you think that abstinence-only education in the U.S. has been responsible for some of the growth in new HIV?

That's a politically charged question. I actually don't know. I don't know that anyone has actually documented that [it was] the abstinence-only education people that have gotten this new growth in HIV infection. I actually think the CDC is doing what WHO is doing; they're trying to come up with better estimates of the number of people infected, and so they may show a larger number now and probably the number last year was underestimated and probably the year before. How do I feel about abstinence-only education? I don't support it. I think that was clear to what you heard me say, that it has to be balanced and that the individuals need to know about alternatives should they not remain abstinent. So whether that has impacted this rise in HIV, no one really knows, and it would be pure conjecture for me to try and answer that.

Should we rethink microbicide research with so much failure?

I think they are doing that and they really are focusing in on active antiretroviral drugs as a microbicide. Cellulose sulfate, nonoxynol-9, some of the other ones, just haven't worked. I don't suspect the ones in current study will have huge effects either. But tenofovir or Truvada might actually work, and CCR5 inhibitors as a microbicide might have an effect. I actually do think they need to rethink that research, get those drugs into the pipeline faster and move forward on that.

So I think I've exhausted the questions here.

Moderator: Ladies and gentlemen, this concludes tonight's teleconference. Thank you for your participation.

This presentation was also webcast on Dec. 12, 2007 and Dec. 14, 2007.

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