• Complications of HIV Disease
• Antiretroviral News
• Conclusions

Eagerly anticipated each year, the Conference on Retroviruses and Opportunistic Infections provides exciting information for members of the HIV community. This year was no exception, and we were fortunate to have two excellent speakers at the February community forum to present Conference news. Michael Marco, an opportunistic infections specialist from Treatment Action Group, and Dr. Roy Gulick, the Medical Director of the Cornell Clinical Trials Unit at the New York Presbyterian Hospital, were on hand to discuss "hot topics" in HIV.

Complications of HIV Disease

Other interesting news in opportunistic infection prophylaxis was presented at the Conference by Ledergerber and colleagues. Currently, it is not recommended that individuals who have had PCP discontinue prophylaxis for the condition, even if they have had a CD4 cell count increase to above 200 cells. Ledergerber's review of 246 subjects with CD4 counts between 277 and 371 who had discontinued secondary prophylaxis showed no recurrence of PCP. This data will certainly influence future prophylaxis recommendations.

Hepatitis News
For individuals coinfected with HIV and HCV, progression rates to HCV-related liver fibrosis (liver scarring) are faster than in HIV-negative people. A group of 172 subjects was examined in a study performed by Bochet and colleagues in order to determine the impact of a protease inhibitor combination regimen on fibrosis progression. The researchers found that the use of a protease inhibitor is associated with a lower fibrosis progression rate in HIV-HCV coinfected individuals. Risk factors for increased fibrosis progression rate include CD4 cell count less than 200, alcohol consumption greater than 50 grams/day (about 5 glasses of wine), and the age at hepatitis infection (people infected when they are older than 20 will progress faster than those infected at a younger age).

Also interesting was a report on the risk factors for Hepatitis C infection in gay men. The prevalence of HCV infection in the group of 232 men studied was higher in HIV-positive gay men, at 14.2%, than in HIV-negative gay men, at 2.7%. While intravenous drug use, low education level, and rimming were all associated with hepatitis C transmission among gay men, the most significant HCV transmission risk factor identified was insertive fisting. Precautions against fluid exchange, such as wearing latex gloves, should be implemented by individuals who engage in fisting in order to lower HCV transmission risk. Proper education regarding this transmission factor is imperative.

Oral Sex and HIV Transmission
In HIV transmission news, a new study by Dillon and colleagues supports the possibility of HIV transmission with oral sex as the only risk factor. 122 individuals with recent HIV infection (within a year) completed a questionnaire regarding their risk behaviors. From the questionnaire only, there were 20 cases out of 122 (about 16 percent), in which the route of HIV transmission seemed to be oral sex. On further interview, other risk factors were identified in all but 8 cases. These eight cases seemed attributable only to oral sex. Although the risk of HIV transmission through oral sex is certainly less than the risk associated with other behaviors, the message that "oral sex is safer sex" requires careful evaluation.

Lipodystrophy Prevalence
A recent examination of lipodystrophy (body fat redistribution) in HIV-positive men and women described the prevalence of body changes (both fat accumulation and fat depletion). 395 patients were assessed in this study, using physical exam as well as patient self-report to gather data. Most of the 324 men and 71 women studied were taking antiretroviral therapy (97% and 94%, respectively), but 19% of the men and 37% of the women were not taking protease inhibitors. Almost all of the women (97 percent) experienced fat accumulation in the breasts, abdomen, neck, or as a "buffalo hump," while 84% of the men studied experienced fat accumulation. Fat depletion (loss of fat in the face, limbs, and/or buttocks) occurred in 77% of the men and in 61% of the women. A combination of the two conditions was reported in 65% of the men and 58% of the women.

A Final Thought
Mr. Marco concluded his presentation with sobering information about superinfection, that is, HIV reinfection with a strain different from an individual's original strain. In a case described by Angel and colleagues, an antiretroviral-naive male with an undetectable viral load whose HIV infection had not progressed for 8 years had sexual contact with another man who had advanced HIV disease and had taken many antiretroviral medications. After their sexual contact, the antiretroviral-naïve man's HIV disease progressed more rapidly, with both an increase in viral load and a decrease in CD4 cell count. Extensive testing showed that the antiretroviral-naïve man had contracted strains of HIV with resistance to protease inhibitors and reverse transcriptase inhibitors from his sex partner. This study has major implications, as it shows that infection with HIV does not necessarily protect an individual from future exposure to HIV (as occurs with other viral infections, like chicken pox). Additionally, this case emphasizes the importance of safer sex practices between HIV-infected persons, as superinfection may lead to more rapid HIV disease progression with fewer therapeutic options.

Antiretroviral News

As an introduction, Dr. Trip Gulick reviewed the current HIV treatment recommendations from the Department of Health and Human Services (DHHS). These recommendations offer guidance on when to initiate therapy for HIV infection and on what antiretroviral medications to use when therapy is initiated. The recommendations suggest that anyone with symptomatic HIV infection (active or past opportunistic infection) begin treatment for HIV infection. Additionally, anyone with asymptomatic HIV (no opportunistic infections) who has a CD4 cell count less than 500 and a viral load between 10,000 and 20,000 copies should be offered treatment. Finally, individuals who have asymptomatic HIV with a CD4 count greater than 500 with a viral load less than 10,000 copies may delay or treat. These recommendations are flexible, as any decision to treat must be based on multiple factors, including the patient's willingness and ability to comply with complicated antiretroviral regimens.

If a decision has been reached by both doctor and patient to initiate therapy, which medications should be used? Medication guidelines from DHHS, based on both effectiveness against HIV and tolerability, are as follows:

Strongly recommended (choose one from column A, one from column B)
Column A	Column B
Efavirenz (Sustiva) Indinavir (Crixivan) Nelfinavir (Viracept) Ritonavir/Saquinavir (Norvir/Fortovase)	d4T + 3TC d4T+ ddI AZT + 3TC AZT + ddI

Recommended Alternatives (choose one from column A, one from column B)
Column A	Column B
Abacavir (Ziagen) Amprenavir (Agenerase) Delavirdine (Rescriptor) Nelfinavir/Saquinavir (Viracept/Fortovase) Nevirapine (Viramune) Ritonavir (Norvir) Saquinavir soft gel (Fortovase)	ddI + 3TC AZT + ddC

Not recommended (insufficient data)
Hydroxyurea (Droxia) Ritonavir/indinavir (Norvir/Crixivan) Ritonavir/nelfinavir (Norvir/Viracept)

Not recommended (substandard therapy)
All monotherapies Invirase (saquinavir hard gel) d4T + AZT ddC + 3TC

With these recommendations in mind, Dr.Gulick reviewed important Conference abstracts pertaining to antiretroviral therapy.

Pharmacokinetics and Drug Development
In order for a medication to be effective against HIV, certain levels of drug must be achieved and maintained in the blood. The dosing schedule for antiretroviral medications is based on the length of time the medication remains in the blood stream. If an individual is not adherent to the regimen, and delays or misses doses, the regimen will not be as effective against HIV. Researchers have been looking for ways to make currently available HIV medications easier to take with once-a-day dosing. ddI is now available in a once-a-day extended release formula and d4T should be available soon. Another exciting option in development is Trizivir, a medication combining abacavir (Ziagen), zidovudine (AZT, Retrovir), and 3TC (Epivir).

A recent innovation in antiretroviral treatment is the use of a small amount of one medication to boost blood levels of another medication. Ritonavir (Norvir) can increase indinavir (Crixivan) levels 10-20 times, and can increase amprenavir (Agenerase) levels 10 times, making combinations with less frequent dosing a possibility. On the flip side, nevirapine (Viramune) decreases efavirenz (Sustiva) levels by a third, and also decreases estrogen and progesterone levels by 29% and 18%, respectively, which is an important consideration for women taking oral contraceptives. Additionally, nevirapine (Viramune), when used in combination with efavirenz (Sustiva), decreases methadone levels, leading to withdrawal-like symptoms.

Salvage Therapy
Many people wonder how to proceed with antiretroviral treatment after a regimen "fails," i.e., the regimen no longer keeps viral load low. ACTG 398 was a large study of a "salvage" regimen containing either saquinavir soft gel (Fortovase), indinavir (Crixivan), nelfinavir (Viracept), or a protease inhibtor placebo in combination with amprenavir (Agenerase), abacavir (Ziagen), efavirenz (Sustiva), and adefovir (Preveon). This salvage study enrolled people who had taken up to three protease inhibitors in the past and had a viral load greater than 1,000 copies. At the end of 24 weeks of treatment, only 34% of subjects had an undetectable viral load (less than 200 copies). The study showed that people who took two protease inhibitors had better results than those who took one protease inhibitor, and that people who had taken NNRTIs (Sustiva, Viramune, or Rescriptor) in the past were more likely to experience failure on the study regimen than were subjects who had never taken NNRTIs. This data may indicate that NNRTIs should not be used in initial treatment for HIV but held for salvage regimens.

Drug Holidays
Recently, researchers have been questioning the potential benefits to patients who, in conjunction with their doctors, decide to temporarily stop therapy. In a study by Deeks and colleagues, treatment was withdrawn in subjects who had experienced an increase in viral load while on a protease inhibitor combination regimen. Among the eighteen subjects who participated in the study and stopped therapy for 12 weeks, a sharp decrease in CD4 cells was observed (the average CD4 cell count at study entry was 245, and the average drop in CD4 cell count was 94). An increase in viral load was also observed. Viruses in most (16 of 18) of the subjects reverted to a type of virus that is not resistant to protease inhibitors, but virus resistant to NRTIs (like AZT, 3TC, and d4T) persisted. These results are inconclusive, and the potential usefulness of drug holidays, if any, is still not understood.

HIV in Women and Children
Dr. Gulick closed his presentation with information culled from studies of HIV+ women and their children. McIntosh and colleagues examined mitochondrial toxicity (damage to the "powerhouses" of human cells) from prenatal NRTI exposure. The examination was sparked by a 1999 study identifying two incidences of fatal mitochondrial neurologic disease in the children of HIV-infected mothers. The two HIV-negative children had been exposed to AZT and 3TC in the womb. McIntosh reviewed five large databases (over 20,000 mothers total) at the NIH and CDC, and analyzed 227 deaths in HIV-uninfected children of HIV-positive mothers. None of these children died of illnesses stemming from mitochondrial toxicity, and only three had symptoms suggesting mitochondrial disease. The three children had not been exposed to NRTIs in the womb. Examination of living HIV-uninfected children will follow.

In a study in Kenya, researchers examined HIV transmission from mother to child through breast milk by comparing HIV transmission rates in breastfed and formula-fed children. The probability of HIV transmission was higher in the breastfed group (approximately 37%) than in the formula-fed group (approximately 20%). Formula use prevented 44% of infant infections, and should be encouraged whenever possible. It should be noted, however, that lack of resources in developing countries makes access to formula difficult, and that malnutrition leading to death may occur if children are not breastfed.

Conclusions
One of the best ways to make informed decisions in your HIV care is to stay abreast of current research presented at scientific conferences in order to initiate discussions with your primary care provider. Use available resources to their fullest extent, and take advantage of treatment education at various organizations throughout NYC.