"It's A Small World After All"

For the past three or four years, it is almost impossible to speak of the "good news" items surrounding the pandemic without at least pausing to reflect on the global situation. I start the list with this perspective. See www.unaids.org for a complete and outstandingly informative report.

Epidemiology statistics remained bleak and cast a pall of sadness or anguish over much of the summer's International aids Conference in Barcelona. Five million people were newly infected in 2001, while 3 million died. (For 2002, the number of deaths rose to 3.1 million.) An estimated total of more than 14 million children live orphaned due to the disease, most of course in sub-Saharan Africa.

The disparity between resource-limited settings and the more developed nations was made apparent throughout the meeting --and the entire year: Several news broadcasts announced that the US gives a the smallest proportion of its gross national product to fight HIV overseas than any other of the world's major economic powers.

Four sub-Saharan African countries have now exceeded seroprevalences of 30%: Botswana (38.8%), Lesotho (31%), Swaziland (33.4%), and Zimbabwe (33.7%). Meanwhile, Eastern Europe and Central Asia have, as the UN aids report termed it, "the unfortunate distinction" of having the highest rates of new infections. As data emerges, the picture grows more dismal: In the Russian city of Togliatti, a focused study revealed that 56% of injection drug users were HIV+, and more than three-quarters did not know of their infection.

On the brighter side, it is known that antiretroviral therapy can cost as little as a dollar a day. Generic formulations are available in some parts of the world as a single tablet. Pharmaceutical companies are moving --alone or together--to make medications available to resource-poor nations.

A World AIDS campaign entitled, "Live and Let Live" is rolling out over the next year, and hopes to recruit more support, medications, and funding, while assuring less discrimination and stigmatization. A group of US physicians, led by Los Angeles HIV-treating physician and hero Charles Farthing, MD of the AIDS Healthcare Foundation, have formed HARPA (Helping AIDS in Resource-Poor Areas).

This organization will be lobbying, advocating, and even sending providers to areas in need. (Last week, after seeing a movie loaded with special effects and costing around $140million to make, I awoke in the middle of the night and started to calculate how many people could be treated with that money.... Then I had to take a sleeping pill....)

Regimens: Simpler Yet

A history lesson is in order here: In 1987, when the first antiretroviral, AZT , was FDA-approved, we would give 12 pills, dosed six times a day (remember the middle- of-the-night alarms?), and this was only one antiretroviral. One was clearly not enough, as we soon saw the emergence of resistance.

Fast forward a decade to 1997, when the most widely prescribed regimen in much of the US was AZT + 3TC + nelfinavir . At a time before the AZT + 3TC had been made into Combivir , and before we dosed Viracept ® twice daily, this regimen wound up being 17 pills, given through three dosings a day!

And now, five years later, with a tremendous marketing push to, simply put, simplify, HAART regimens, we have options such as Videx-EC + tenofovir ( Viread ) + Sustiva--a complete HAART regimen dosed as three pills one time daily! (There are several other options which employ once daily dosing, and the very patient-friendly Trizvir , one pill twice daily, etc.) Although studies have not yet validated the parity of such a regimen with a more conventional one, patients' viral loads staying suppressed and t-cells staying buoyant are some rather promising surrogate markers.

Sustiva Rocks!....

Several of the studies presented at July's Barcelona Conference firmly planted efavirenz (Sustiva) as a fine, if not the best, choice for the third drug to join the nucleoside backbone in a HAART regimen.

Actg 384 compared six different HAART regimens, and found that efavirenz was superior to the protease inhibitor which had been the most widely prescribed at the time of the study onset--nelfinavir (Viracept®)--when the nucleoside backbone was AZT + 3TC.

The CLASS study, also presented at this Conference, compared three regimens, each with a backbone of 3TC + abacavir ( Ziagen ®), and a randomized third drug. This study also validated the superiority of Sustiva® in comparison to d4T ( Zerit ®) and a boosted protease regimen ( amprenavir + ritonavir ) as the options for the third drug. Besides its virologic efficacy, Sustiva® is also seen as advantageous for lower incidence of lipodystrophy and other (e.g. cardiovascular) side effects--except for the cns, where it racks up points in a major way--and ease of dosing.

A lingering and important question-- which should be answered in a few months--is this: Since many studies have compared Sustiva® to nukes and pis, how does it stand up in comparison to its closest cousin--the other widely prescribed non-nuke, nevirapine ( Viramune ) ? The results of the "2n" study, a multi-center randomized head-to-head comparison of the two, will be presented at the Tenth Conference on Retroviruses and Opportunistic Infections, in early February.

...Unfortunately, So Does Syphilis

"Unabated" is the term which the County of Los Angeles recently used to describe the ongoing syphilis outbreak, for which a majority of cases are occurring in men who have sex with men (MSM). In all of 1999, there had been 120 cases of syphilis in the County (with comparable rates seen in MSMs versus men who have sex with women (MSW)), up to 337 and 399 in 2000 and 2001 respectively. By November 15 of this year, there had been 445....

A majority of the cases in the MSM population occur in men who are also HIV+. The equation here is an easy one to decipher, but for many, a more difficult one to comprehend: Men with HIV are having frequent unprotected sex with other men.

If the spread continues, it could have significant health and political implications: Did you know that if you have syphilis, you have a greater risk of acquiring HIV if you have sex with someone who is HIV+? And if you are HIV+ and also have syphilis, you are more likely to infect your partner with both HIV and syphilis?

The initial primary lesion of syphilis, a small ulcer called a chancre, is painless, disappears within a few days, and thus often goes unnoticed. The disease is known to progress more rapidly in HIV+ people to secondary and even tertiary stages, and may be more difficult to treat. Also, most people with HIV who also get syphilis will need to have at least one lumbar puncture (spinal tap) done for proper diagnosis and surveillance.

If you have engaged in unprotected sex over recent weeks or months and get a diffuse body rash, be sure to tell your provider, and be tested for syphilis, which, unlike HIV, is curable! Most HIV providers in the County are doing regular testing (a simple blood test, called a vdrl or rpr) in MSM. I would also venture to guess that if these rates keep up, the voices that would close down sex clubs and bathhouses will be revved up by many decibels--with political support behind them. (Sound like the mid-1980s? Yep....)

The Heart and HAART

Ever since 1998, when providers began to observe what seemed to be a disproportionate number of HIV+ individuals having heart attacks at a young(er) age, studies have attempted to define the risk and, hopefully, quell the panic. Protease inhibitors were seen as being most responsible. Several studies presented at February's Retroviral Conference in Seattle, as well as others from the International Conference in Barcelona, shed light on the issue--but we are still a ways from definitive answers.

Here's some of what we know: The US Veterans Cooperative Study, which has the largest database of HIV+ people in the country (more than 36,000) reported last winter that there was no significant increase in cardiovascular hospitalizations in that huge cohort. A Kaiser Permanente cohort, however, found an increase in cardiovascular-related hospitalizations in HIV+ people, but no difference amongst treatment types (untreated versus non-pi versus pi were all comparable).

A study from the University of Cincinnati did show a higher rate of progression to coronary heart disease in HIV+ versus HIV-negative people, and also a higher rate in protease-treated. (Confusing? Yes....) However, this study also illuminated a related and important issue: 34% of the HIV+ people were smokers, versus only 18% of the uninfected.

The International Conference added to the data pool--an Italian which clearly imputed pis as being much more linked to heart disease--and made headlines worldwide --has since then been retracted due to the likelihood that the data was "fudged." However, an observational study from the well-respected hops cohort did show a statistically significant increase in actual heart attacks (although not in angina pectoris or in strokes) in HIV+ people.

What can we take away from this accumulation of numbers and reports at this time?

First, the numbers, even when they are statistically significant, are small; we're talking a handful of heart attacks here-- virtually everyone agrees that the benefits to longevity of HAART therapy, when indicated, are still much greater than this possible downside.

Whether this is right or wrong will be borne out in time--but, many believe that avoiding protease inhibitors , especially in people with other risk factors, may minimize the risk altogether.

And, relatedly, everyone also agrees that if you have HIV, you should work vigorously to reduce known risk factors: Stop smoking. Control elevated cholesterol and triglycerides. Control high blood pressure and diabetes, if they exist. Exercise and eat right.

California and HIV: A "Legal" Year

Exactly halfway through the year, on July 1, two regulations involving the epidemic in this state were activated:

First, HIV became a reportable condition --although using a non-name "Soundex" coding system. California, which has onesixth of the aids (and perhaps HIV, too? [now we will know...]) cases in the US became the 48th or 49th state to have some form of reporting. (New York, and perhaps one other, still remain without such a system.)

After years of debate between epidemiologists ("How can we treat this epidemic if we don't know where the people who are infected are?") and community activists ("This will drive people away from testing and from treatment, for fear of discrimination."), the decision was made that HIV can indeed be best dealt with if the age, gender, ethnicity, and zip code of infectees is known. Health care organizations and laboratories alike scrambled to put into place the systems which would enable compliance with the regulation.

To keep up with the tracking efforts of HIV within the state, go to www.dhs.cahwnet. gov/aids/ Then, lobbying efforts on the part of people living with HIV and their advocates led to a regulation that an HIV+ member of a health care organization can be referred directly to an HIV specialist and cannot be denied access to such. The regulation, however, did not officially define just what is "an HIV specialist." Two competing organizations-- the American Academy of HIV Medicine, and the HIV Medicine Association of the Infectious Diseases Society of America--have come up with definitions and providers around the State are becoming certified.

Hepatitis: It's "B" As Well As "C"

Attention this year shone as brightly as ever on the coinfection of hepatitis c (hcv) with HIV, but also more words and presentations were given to hepatitis b coinfection. First, on "c," an estimated 40% of the more than 35 million people worldwide who have HIV also have hepatitis c. (In injection drug users cohorts, the percentage is more than 60%, and in some studies, exceeds 90%!).

Basically, all HIV+ people should be screened for hcv. The presence of HIV may accelerate the course of hcv, and thus consideration should be given to treating the hcv. (Data released in Barcelona affirmed that HAART reduced mortality in coinfected patients.)

Combination pegylated interferonalfa (Pegasys) along with ribavirin (Copegus) was FDA-approved in early December for treatment of hepatitis c-- and so far has shown the best rate of sustained virologic response (svr) of various treatments used.

The coinfection rate of hepatitis b and HIV is lower, perhaps 5%-10% in the US, but also carries significant clinical implications. (There is of course a preventative vaccine for b, unlike for c, and thus the screening of all HIV+ patients is a must.)

The commonly used anti-HIV 3TC is one of three drugs FDA-approved for hepatitis b treatment. The others two are interferon-alfa, and the recently approved Hepsera. (This drug is actually adefovir, which failed as an HIV treatment due to kidney damage, but in a much lower dosage has been shown to suppress hbv without damaging the kidneys.

Two Drugs in Expanded Access

"It feels like the 90s all over again," one HIV+ patient recently told me--due to the simultaneous availability of t-20 (Fuzeon) and atazanavir (Zrivada).

T-20, shown to decrease viral load by around 1 log when added to an optimal background regimen, is the first of a new class of drugs to be considered for FDA approval.

It is a fusion inhibitor--high-tech (must be injected twice daily) and expensive--and may provide a respite for people who have been failed by the 16 available antiretrovirals.

Atazanavir is a protease inhibitor which so far shows the potential to not elevate lipids the way protease inhibitors often do. It also boasts the ease of doing two pills taken once daily. (Yes, even pi-containing regimens can be simplified!). The risk of elevated bilirubin, which, while not dangerous to the body, can make one jaundiced, may cut into its promise. Stay tuned to next year, when this should be freely available, too. (If you are failing on currently approved medications, speak to your provider about receiving either or both of these expanded access drugs. Fuzeon® is in limited supply and may be much harder to obtain.) History note here: It was the HIV epidemic, and the efforts of advocates and activists, which led to the first expanded access drug program--remember "Parallel Track" and ddI prior to its 1991 FDA approval?

Where Do We Go with HPV and Anal Dysplasia?

This is one of those issues which keeps getting talked about...and talked about....

We know now that people with HIV, who also have a higher incidence of human papillomavirus (hpv)--which causes venereal warts--may be in line for an increased risk of anal pre-cancers and other cancers. The numbers, here, too, are small, but one writer (Richard Ferri, PhD, in the HIV publication Numedx.com) called it "the silent disease."

We also know that routine anal pap smears would be a good way to detect these in early stages. But...we don't yet know the answers to many of the relevant questions: Exactly who should be screened (all HIV+s? only those with HPV? women as well as men?) and how often?

When should a specialized procedure called colposcopy be done? Who will do it? What should be done when a "dysplastic" cells (not cancerous, but could eventually become such) are found? Just observe closely, or treat more aggressively? When anal cancer exists, what is the best treatment (radiation? chemotherapy? surgical excision?)?

To paraphrase one HIV expert I heard at an International AIDS Society meeting I attended in November: "We can all start by doing inspections and digital rectal exams more frequently than we are now, and gradually increasing our use of anal pap smears."