The first conference on the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) for the 21st century held promises for the future of HIV disease both in improvements in medical management and the promise of a vaccine. The theme of the 7th Conference on Retroviruses and Opportunistic Infections was "At the birth of a century, research toward ending AIDS."
The vaccine search continues for HIV as well as hepatitis C (HCV). Finding a vaccine that works appears to be an important goal for the next several years. Several new antiretroviral therapies (ART) are in the pipeline and presentations and posters on the use of IL-2 to improve immune response were in abundance. The level of interest in metabolic dysregulation continued with several sessions. This article will provide an overview of those events that appeared to be important and/or show promise for the future of treating HIV disease.
Investigators in San Francisco presented a poster showing that transmission through unprotected oral sex does occur. In fact, oral sexual transmission of HIV may actually occur more often than had previously been thought. Of 20 cases it was suspected that 8 were most likely to have been transmitted though unprotected oral sex.
Also presented was the first documented case of reinfection with another strain of HIV in an HIV-positive individual. The subject was a man, diagnosed in 1989, who had had stable T-cells of 700 for several years and was not on antiretroviral medications. This patient became reinfected by his HIV-positive partner with a resistant strain of HIV after having unprotected anal sex. Reinfection lead to a dramatic decrease in CD4 T-cells and an increase in his viral load of greater than 400,000 copies/mm3. Reinfection with another strain of HIV has always been thought to occur; however, this hypothesis had never been validated until now. This should serve to reinforce the importance of condom use between concordant couples, in which both partners are HIV-positive, as well as sero-discordant couples, in which one partner is HIV-positive and the other is HIV-negative.
Vaccines are not looking very promising, and researchers do not seem any closer to the development of a vaccine. Out of 70 phase I clinical trials, only two vaccines are now in phase III clinical trials. The new direction of vaccines may lean toward using IL-2 to improve the immune's response to an HIV vaccine. But researchers felt that it may be several years before a vaccine is found that effectively restores immune response against HIV and/or prevents HIV transmission.
Hepatitis C (HCV) is receiving a great deal of attention. Several oral presentations and posters implied that understanding the total picture of HCV is several years behind HIV. Clearly there is concern about the risk of patients who are co-infected with both HIV and HCV and the increased risk of developing hepatic carcinoma.
Presentations on adherence concluded that healthcare providers tend to overestimate their patient's adherence and that patient self-reporting is much more precise. Not surprisingly, the impact of direct observational treatment (DOT) on virologic outcomes was superior to self-administered meds.
New drugs that are more effective, less burdensome, and less toxic are still needed. Several new potential targets in the treatment of HIV infection were presented; they included chemokine receptors, fusion inhibitors, and integrase inhibitors.
T-20 fusion inhibitors are currently in phase II/III development; however, due to their chemical make-up, they will require injections twice daily. T-1249, which has shown to be active against T-20 resistant strains, is in phase I trials. New antiretroviral agents presented at the conference included ABT-378, Tipranavir, BMS 232,632, MK 944A (currently on hold for kidney toxicities), AG1776, PD178390, and Dupont's PI. With the exception of ABT-378, none of these drugs will become available outside of research until late this year or next. In the NRTIs, DAPD, tenofovir, and FTC are currently in clinical trials. The new drugs in the NNRTI class are capravirine, Dupont's 961, and 083. Intensification with tenofovir appears promising and a small pilot study looked at a once-a-day dosing of FTC, ddI, and efavirenz. This may show promise in the future by decreasing pill burden and simplifying current drug regimens.
The WIHS and MAC studies, which showed that women have lower viral loads than men, was presented last year, at the 6th Retroviral Conference. During the last year, these findings were confirmed by the Center for Disease Control and Prevention's (CDC) study of 3776 antiretroviral-naïve women and men. This study showed that women had 50% lower viral load than men and that gender is not associated with difference in time to AIDS-related opportunistic infections. The question still needs to be addressed: should the antiretroviral guidelines be changed to reflect these findings in differences in viral load and beginning antiretroviral therapy (ART) earlier in women than men-
Several oral and poster presentations provided information that suggests that we still do not understand lipodystrophy syndrome (LDS). An oral presentation by Kathleen Mulligan suggested that HIV-negative and HIV-positive individuals who were not receiving ART showed no difference in body composition, as demonstrated on a DEXA scan. However, examination of those individuals taking ART, whether the drug combination contained a protease inhibitor (PI) or not, showed evidence on a DEXA scan for clinical LDS. The group who complained about fat accumulation had the most significant changes in overall body composition. It is not clear at this point in time whether this will mean anything clinically. The take-home message is that we still do not clearly understand the pathophysiology of this syndrome and that it may be multifactorial.
Several studies have suggested that gender differences exist between men and women with regard to metabolic and body changes. One study, which looked at women and men when treated with a NRTI combination without a PI, showed that women may have more fat accumulation than men and that men may have more fat loss than women.
Risk factors for developing LDS included age greater than 40 years, being HIV+ for more than 7 years, a diagnosis of AIDS for more than 2 years, and being a hemophiliac. Perhaps PI and NRTI are a risk factor and not the sole cause. Early studies reported lipid abnormalities in HIV-positive patients more than 10 years ago (1988, before mass ART use). Insulin resistance has been seen in 25% of patients just on NRTI, suggesting that NRTI may also play a role in LDS.
Treatments for LDS have included lifestyle changes, nutritional changes, exercise and surgical interventions without a definitive difference at this point in time. However, more studies with larger numbers of study participants in well-controlled clinical trials are needed to show a difference between rigorous exercise and diet modifications. Metabolic abnormalities and fat distribution are not always linked, no consensus on a case definition currently exists and may be multifactorial, and currently there are no clear recommendations to treat LDS. Changing a PI containing medication regimen for a NNRTI or NRTI regimen does not appear to change LDS based on several small study reports. Further studies are needed.
Several posters presented information about patients with metabolic complications with high triglycerides and cholesterol and their risk for developing arterial atherosclerosis plagues (the disease that can lead to a heart attack or a stroke). Another poster presented a study conducted at USC on 15 HIV-positive women paired with 15 HIV-negative women. Despite the HIV-positive women presenting with higher levels of lipids, there was no difference in the thickness of the carotid arteries based on intima media thickness as measured by carotid UTZ (ultrasound), suggesting no increased risk of developing artherosclerotic-associated disease. However, this was a small number of patients, and more information needs to be collected. A large-scale trial is scheduled to begin later this year.
Another interesting poster presented information on the potential increased risk of hypertension (HTN) in individuals with LDS. In a small case-controlled prospective trial, individuals with LDS had a 40% increase in elevated blood pressures.
Osteopenia (thinning of the bones) was an interesting finding in a 74-patient cohort receiving HAART. Osteopenia was found in patients who presented with lipodystrophy and was reported in patients not receiving any medication treatments, but appeared more common in those patients taking medication. Additional information is needed before a determination can be made as to the cause.
Methadone may cause problems for those individuals who require this drug and are concurrently on a PI or NNRTI regimen. These patients should be monitored very closely for potential methadone withdrawal because of the lowering effects of most PIs and NNRTIs.
IL-2 is showing promise to potentate the replication of CD4 cell counts. Several presentations looked at the administration of IL-2 in patients who have viral suppression on currently stable ART therapy for a minimum of four months. When compared to a control, patients receiving IL-2 had a significant increase in CD4 with viral loads that remained undetectable.
Switching medication therapies from a protease-containing regimen to a regimen containing either abacavir or a NNRTI after viral load goes below 50 copies/mL was the subject of several posters. The data is still very limited; the most extended study measured viral loads for 48 weeks. There is about an overall 10% failure rate in this study in the NRTI arm, but not in the NNRTI regimen. Changing medication to a maintenance therapy may require fewer pills and less complex regimens and may offer an improvement in dosing. Again, adherence is extremely important in maintaining durability of any medication regimen.
Up until recently, only genotyping information was available. However, a poster was presented looking at HIV-1 resistance testing (VIRA 3001 trial). This trial randomized patients to either standard of care (T-cells and viral loads) or phenotyping. The study showed that phenotyping may add another piece of information in appropriate management of patients infected with HIV. Questions that still need to be answered include does phenotyping offer more than genotyping and how do the results translate into clinical benefit for the cost (test cost between $450 to $900 per test)-
Attendees of the first conference of the 21st century did not leave feeling that they were any closer to preventing, eradicating, or vaccinating for HIV. Many questions continue to hang in the forefront of everyone's mind. Researchers, providers, and patients are still searching for the right initial medication regimen, how to improve adherence, and what to do with patients who are failing or intolerant to currently available medications. Perhaps as the World AIDS Conference 2000 rapidly approaches, more information will be presented that offers solutions to the current AIDS epidemic.