Safe Steering and the Global AIDS Crisis

Bill Gates, founder of Microsoft, opened the 9th Conference on Retroviruses and Opportunistic Infections (9th CROI) as keynote speaker by comparing the AIDS epidemic in Africa to the sinking of the Titanic. This analogy is extremely apt, for not only is it proving difficult to gauge the severity of the epidemic by examining the tips of the icebergs (those known to be infected), but it also appears that the number of lifeboats on board (available treatments) is inadequate to ensure the safety of all the passengers. Although Bill Gates did not elaborate further, he clearly implied that passengers in steerage may not be aware of existing disparities between their chances of survival compared to passengers holding a higher class of ticket. He invoked philanthropy as one potential solution to the global AIDS crisis, and asked every conference participant to view those afflicted by HIV/AIDS as their neighbors in the world village and to engage in the battle against AIDS on pure humanitarian grounds.

This article will review aspects of the 9th CROI relevant to the management of HIV and hepatitis in correctional settings. The impact of research reported at the CROI on the current management of HIV infection, as summarized in HHS guidelines (last updated Feb. 4, 2002), will also be presented.

Starting Controversy

In only a few short years, recommendations on initial antiretroviral treatment in the treatment-naïve individual have completely changed course. In 1996, the "hit early, hit hard" approach to HIV management was unveiled by David Ho and colleagues at the World AIDS conference in Vancouver. Their recommendation for early, intense therapy was based on the results of mathematical models that predicted that HIV infection could be eradicated from infected cells in a matter of years if viral replication were completely suppressed.¹ Unfortunately, these early models of HIV replication were flawed because it was not known at the time that HIV could persist for decades in resting T cells, macrophages, and other "sanctuary" sites. It is now recognized that this persistent virus is a source for renewed viral replication and infection of other cells when HAART is discontinued.²

Gradually, optimistic sessions on "HIV Eradication" at the annual CROI meeting have given way to sessions focusing on optimizing the durability of therapeutic response and limiting drug toxicity using strategic treatment interruption (STI), immunotherapy, and other strategies which reduce exposure to or even obviate the need for antiretroviral therapy.³ This year, initial hopes for interrupted therapy were dashed as STI was put to "R.I.P." (rest in peace) by Bernard Hirschel, who summarized data from the Swiss Spanish Intermittent Therapy Trial (SSITT).⁴ Reports on the long term side effects associated with HAART also became more numerous (Adverse Events will be covered in Update Part Two in the June/July issue of HEPP News; Volume 5, Issue 6/7).

In the "Controversies" session of the CROI conference, Richard Chaisson, M.D., of Johns Hopkins University raised another note of caution and proposed that we temper our enthusiasm for early treatment by considering the potential for treatment-related adverse events along with new data on patient outcomes when deciding when to initiate treatment.⁵ This more cautious approach to the initiation of HAART is also reflected in the most recent version of the HHS Guidelines for the management of HIV infection in Adults and Adolescents6 (Table 1): "While randomized clinical trials provide strong evidence for treating patients with <200 CD4+ T cells/mm³, the optimal time to initiate antiretroviral therapy among asymptomatic patients with CD4+ T cell counts >200 cells/mm³ is not known. For individuals with >200 CD4+ T cells/mm³, the strength of the recommendation for therapy must balance the readiness of the patient for treatment, consideration of the prognosis for disease-free survival as determined by baseline CD4+ T cell count and viral load levels, and assessment of the risks and potential benefits associated with initiating antiretroviral therapy."⁶

An important new concept that was discussed at the meeting was the "AUC" or "area under the curve" for HIV viral load. There appears to be a good correlation, as expected, between viral load AUC and clinical outcomes. It should come as no surprise that lower viral load AUC (fewer detectable viral loads or lower viral loads measured at several time points during therapy) were directly correlated with patient adherence and combination therapy potency. This relationship between adherence and outcomes is emphasized in the HHS guidelines: "patient readiness" is to be used as a key determinant for initiating therapy.⁶

Starting at <200 CD4

Due in part to the ability of HAART to lower viral loads for prolonged periods of time, new data from longitudinal cohort studies appears to demonstrate that delaying HAART may not be detrimental in the context of the current standard of HIV care in developed countries (in Europe, the US or Australia, where the cohort studies were located). One study by a group in Europe⁷ showed that virologic suppression can be achieved even when starting HAART at CD4+ T cell <200, and that the level of virologic suppression achieved was equivalent to starting HAART at >350. At first glance, this appeared to contrast with another report by Sterling et al., which indicated that starting HAART at higher CD4+ T cell appeared to be associated with improved clinical outcomes.⁸, 9 However, Richard Chaisson, one of the investigators, pointed out that even in this study, the beneficial effects of early treatment were eliminated when controlling for the viral load AUC.⁵,8 In other words, patients who achieved similarly low viral loads did equally well whether they were started at <200 or <350.⁸ Dr. Chaisson was emphatic, stating "Patients started on antiretroviral therapy with CD4+ T cell counts >350 are likely to experience considerable toxicity as well as emergence of drug-resistant virus in the absence of a compelling clinical benefit. Initiation of therapy should be based on CD4+ T cell count and the patient's ability to comply with complex and potentially toxic regimens."⁵

Starting at >350 CD4

In contrast, several clinical studies presented at the 9th CROI appeared to demonstrate that earlier HAART initiation (at CD4+ T cells >350) might be advantageous. David Cooper, from the Sydney (Australia) AIDS group¹⁰ showed that immune function could be restored in patients who started HAART later, but the durability of the restoration might be decreased. In that study, as in the EUROSIDA study, baseline CD4+ T cell count at initiation of therapy determined which patients would achieve CD4+ T cell counts above 500 cells/mm³ with HAART.¹¹ Another study by the Hopkins group (Palella et al.) showed that initiation of HAART at CD4+ T cell 201-350/mm³ was associated with reduction in mortality in comparison with patients for whom HAART was delayed until they reached a lower CD4+ T cell count.¹² Thus, individual clinicians will need to continue to use their discretion when considering when to start therapy. Perhaps all of these studies are best interpreted as indicating that patients who are highly motivated (and expected to achieve lower viral load AUC) might choose to initiate therapy at lower CD4+ T cell counts (<200) and still achieve excellent virologic response. Delaying therapy may have other important effects on the overall epidemic: (1) HIV is more easily transmitted by persons who are HIV infected and not on treatment and (2) delayed treatment may impair the reconstitution of anti-HIV immune responses - which may become more important as therapeutic HIV vaccines advance to Phase III trials. The bottom line is that the whole patient (medical status, psychosocial context, motivation, etc.) must be considered.

Despite these revisions to the guidelines, not all HIV treaters are convinced that delayed treatment is the optimal strategy. As Brigitte Autran (Pitié-Salpétrière, Paris, France) explained in her opening day plenary talk, HIV immunopathogenesis data seems to indicate that starting HAART earlier may preserve T cell responses that are specifically directed against HIV, which are associated with better control of chronic infection.¹³ In her plenary talk on immune restoration, Autran postulates that the early recovery of anti-opportunistic infection (OI) CD4+ T cell response is due to the presence of chronic OI. She provided data showing that Tetanus, CMV, and Candida responses return after HAART, but not with anti HIV-specific help: the CD4+ T cells specific for HIV that had been erased soon after primary infection do not reconstitute, while the preexisting CD8+ T cells decrease in direct proportion with the viral load.¹³ Such data, as well as information presented at the 9th CROI on once-a-day regimens and 2nd generation ART drugs with fewer side effects, may eventually re-shift treatment recommendations towards earlier (>350 CD4+ T cells/mm³) treatment in the future.

Impact of Clinical Care

In what now appears to be an annual update on the impact of access to specialty care in HIV morbidity and mortality, Kitahata and colleagues reported that the risk of HIV disease progression and death was determined by whether or not patients received HAART within 12 months of their initial clinic visit (this study cohort consisted of 238 patients receiving care at a university-affiliated HIV clinic). CD4+ T cell counts were also an independent risk factor for disease progression. Patients with CD4+ T cell counts < 200 cells/mm³ were at significantly greater risk of disease progression than patients with higher CD4+ T cell counts, even if antiretroviral therapy was started. These data again suggest that starting therapy sooner rather than later may be beneficial regardless of the CD4+ T cell count.¹⁴

Adverse Effect Accumulation

Part of the dampening of enthusiasm for early treatment at the 9th CROI is due to accumulation of data on adverse events associated with HAART. The list of adverse events associated with HAART now includes: lactic acidosis/ hepatic steatosis, HAART-associated hepatotoxicity, fat maldistribution or lipodystrophy, hyperlipidemia, osteopenia, skin rash, and new additions to the HHS guidelines: hyperglycemia, osteonecrosis, and osteoporosis. And, as shown in the HIV 101, the list of serious side effects (issued as "black box" warnings by the FDA) is growing, with the recent addition of NNRTI-associated hepatitis (nevirapine) and NRTI-associated lactic acidosis in association with Guillain-Barré- like neurotoxicity following severe lactic acidosis (as reported at the 9th CROI). Skin rash has now become a class-related adverse event (associated with NNRTIs).

Emerging Resistance

Reports at the 9th CROI also raised concern about the impact of drug resistance on future HAART therapy. This concern is reflected in the new emphasis in the HHS guidelines on genotyping at initiation of HAART for individuals in whom acute HIV infection is diagnosed. For example, Bennett and colleagues studied 923 recently diagnosed people in 10 US cities (1998-2000) and noted that resistance to 1 or more antiretroviral from any class increased from 3.8% to 9.0% during the study period.¹⁵ Grant and colleagues evaluated viral genotypes in 225 recently infected individuals in San Francisco, California and found that resistance to any class of drug increased from 16.7% to 27.6% between July 1996 and 2001.¹⁶ In contrast, investigators in Sydney, Australia, failed to observe such an increase.¹⁷ The new HHS guidelines reflect concerns about the impact of drug resistance on response to initiation of treatment: "Transmission of drug-resistant strains of HIV has been documented, and may be associated with a suboptimal virologic response to initial antiretroviral therapy. If the decision is made to initiate therapy in a individual with acute HIV infection, optimization of the initial antiretroviral regimen through the use of resistance testing is a reasonable, albeit untested, strategy. Because of its more rapid turnaround time, the use of a genotypic assay may be preferred in this setting."⁶

Interrupted therapy and Immunity

As is well known, in the course of chronic infection, HIV specific T cells are extremely activated and active, located in proximity to dendritic cells (DCs) that not only present HIV specific epitopes (which activate them) but also have live virions on their surface. Therefore the DCs simultaneously activate and infect CD4+ T helper cells - which then, in turn, become the target of HIV-specific CD8+ cytotoxic T cells (CTL). This leads to the preferential depletion of CD4+ T cells specific for HIV, as has been described by a number of expert HIV immunologists including B. Autran and Bruce Walker. The process is termed "depletion of HIV-specific T helper cells" and is a critical issue at the heart of controversies related to initiation of HAART, STI, and therapeutic vaccination.

What happens to the HIV specific CD4+ T cells? After interruption of HAART (as with STI), Autran, speaking in the plenary session, saw increases in HIV specific CD4+ T cells that were associated with the rebound in viremia. The CD4+ T cells rebounded even before the virus was detectable, and, alarmingly, usually disappear before the treatment was re-introduced. She postulated that these HIV-specific CD4+ T cells are immediately eliminated (either by HIV-specific CD8+ T cells or by the direct destruction of the cell due to viral replication). Thus, Autran says that STI may actually be problematic - because as each wave of CD4+ T cells is re-introduced, they are wiped out by the HIV-specific CD8+ T cells. This observation has major implications for patients who undergo periods of "Unstructured Treatment Interruption" such as those individuals who cycle through correctional facilities. Furthermore, given this information, STI is bound to fail.

A related report at the 9th CROI demonstrated the co-evolution of antibody responses and viral escape, in waves, during infection. Using a novel HIV entry assay, Richman and colleagues evaluated the co-evolution of HIV envelope and neutralizing antibody from plasma following primary HIV-1 infection. Most patients (12/14) rapidly generated strong neutralizing antibody responses to autologous virus. However, each sequentially replicating generation of viruses consistently and rapidly escaped the concurrent neutralizing antibody response by developing mutations in the RNA sequences that code for the neutralizing epitopes. The rate of viral neutralization escape was remarkable and indicated that neutralizing antibody can exert a previously unappreciated level of selective pressure on viral evolution. These data have important implications for natural history and vaccine development.¹⁸

Stopping Therapy

In a report from CROI that was very relevant to HIV care in corrections, the EUROSIDA group evaluated the impact of stopping antiretroviral therapy. They evaluated the clinical outcome of 565 patients in the EUROSIDA study who interrupted HAART on their own. Of the 565, 49% have restarted therapy, and 290 developed a new AIDS Related Event (ARE) or died. Twenty-eight of these events occurred after being off therapy for at least 3 months (28/140 person-years = 0.20 per person-year). The relative hazard of a new ARE or death associated with having been off therapy for at least 3 months was 2.4 (95% CI 1.6-3.6; p=0.0001) after adjustment for the latest CD4+ T cell count and viral load. These data indicate that risk of AIDS and death increases more than two fold upon therapy interruption or stopping. The absolute risk remains closely linked to the latest CD4+ T cell count and was highest among patients with a latest CD4+ T cell count below 200/mm³.¹⁹

Detecting HIV

Perhaps the most important role that corrections plays in the global AIDS crisis is the role of testing and educating HIV-infected individuals. At the 9th CROI, Fleming and colleagues from the Centers for Disease Control and Prevention (CDC) reported on the continued spread of HIV in the United States. They estimated that in 2000, between 850,000 and 900,000 people in the United States were living with HIV infection, and 40,800 people acquired infection. A substantial number of people with HIV infection (between 180,000 and 280,000) are unaware of this fact, further increasing the risk for transmission.²⁰

Perhaps more importantly, it is still clear that many HIV-infected subjects do not know their status. The goal of the CDC's Project SAFE (Serostatus Approach to Fighting the Epidemic) is to bring people into care and counseling earlier.²¹ Unfortunately, it now appears that treatment of HIV-infected individuals is to be delayed until they achieve lower CD4+ T cell counts, leading to the inevitable question from the patient: Why get tested? Clearly, because there are so many individuals who are unaware of their infection, it is important to continue to test individuals for HIV. This is particularly true in corrections, a setting with which many people at high risk for HIV infection come into contact. While the patient may not see the benefit of getting tested for HIV, the correctional health care provider must continue to encourage testing of individuals at risk for infection. Returning to the image of the Titanic proposed by Bill Gates, reports presented at the 9th CROI leave us lost at sea, surrounded by dangers that are half-perceived. The best advice for correctional health care providers may be to stay tuned in for more changes in course as our understanding of HIV continues to evolve.

Table 1

References

* Consultant & Speaker's Bureau: Abbott, Agouron Pharmaceuticals, Merck, Roche, Boehringer-Ingelheim, Schering Plough

** Consultant and Speaker's Bureau: Abbott Laboratories, Boehringer Ingelheim, Roche, Agouron, Bristol Myers Squibb, GlaxoSmithKline, Gilead Sciences, Ortho Biotech and Merck Pharmaceuticals.

1. Perelson AS, Neumann AU, et al. "HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time." Science 1996 Mar 15;271(5255):1582-6.

2. Finzi D, Hermankova M, et al. "Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.", Science 1997 Nov 14;278(5341):1295-300.

3. STI was reviewed in HEPP News, October 2001; 4(10).

4. Hirschel B, Fagard C et al. "SSITT: A Prospective Trial of Treatment Interruptions in HIV Infection" Abstract 528-M and Hirschel, B. "Strategic Treatment Interruptions: Where Are We?" Abstract S18, 9th CROI, February 24-28, 2002, Seattle, WA.

5. Chaisson, R. Session 21 Symposium. R. E. Chaisson, "When to Start Antiretroviral Therapy?" Abstract S17, 9th CROI.

6. HHS Adult and Adolescent guidelines for Antiretroviral Therapy, available at http://www.hivatis.org/guidelines/adult/Feb04_02/AdultGdl.pdf

7. Phillips AN, Staszewski S, et al. "HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load." JAMA 2001 Nov 28;286(20):2560-7.

8. Sterling TR, Chaisson RE, et al. Session 66, Poster 469-M. 9th CROI.

9. Chaisson RE, Keruly JC, et al. "Association of initial CD4 cell count and viral load with response to highly active antiretroviral therapy." JAMA 2000 Dec 27;284(24):3128-9.

10. Kaufmann GR, Cunningham P, et al. "Impact of early HIV-1 RNA and T-lymphocyte dynamics during primary HIV-1 infection on the subsequent course of HIV-1 RNA levels and CD4+ T-lymphocyte counts in the first year of HIV-1 infection. Sydney Primary HIV Infection Study Group." J Acquir Immune Defic Syndr 1999 Dec 15;22(5):437-44.

11. Kaufmann GR, Bloch M, et al. "Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy." AIDS 2000 May 26;14(8):959-69.

12. Palella F, Knoll M, et al. "Lower Mortality in Ambulatory HIV-Infected Patients who Initiate Antiretroviral Therapy at Higher CD4+ Cell Counts" Session 5, Oral Abstract 13. 9th CROI.

13. Autran, B. "Immune Reconstitution and Immunologic Responses to Antiretroviral Therapies: Implications for Therapeutic Strategies." Plenary Session 3, 9th CROI.

14. Kitahata M, Dillingham P, Van Rompaey S. "Initiating Potent Combination Antiretroviral Therapy within 1 Year of the First Clinic Visit for Patients at All CD4 Cell Count Levels Is Associated with Better Long-Term Outcomes" Abstract 467-M. 9th CROI.

15. Bennett D, Zaidi I, et al. "Prevalence of Mutations Associated with Antiretroviral Drug Resistance among Recently Diagnosed Persons with HIV, 1998-2000" Abstract 372. 9th CROI.

16. Grant RM, Kahn J, Warmerdam M, et al. "Transmission and Transmissibility of Drug Resistant HIV-1" Abstract 368-M. 9th CROI.

17. Ammaranond P, Cunningham P, et al. "No Increase in Protease Resistance and a Decrease in Reverse Transcriptase Resistance Mutations in Primary HIV-1 Infection: 1992-2001 Sydney, Australia" Abstract 370-M. 9th CROI.

18. Richman DD, Wrin T et al. "Rapid Evolution of the Neutralizing Antibody Response following Primary HIV Infection" Session 10, Oral Abstract LB5. 9th CROI.

19. Lundgren JD, Vella S, et al. "Interruption/Stopping Antiretroviral Therapy and the Risk of Clinical Disease: Results from the EuroSIDA Study." Session 13, Oral Abstract 48. 9th CROI.

20. Fleming PL, Byers RH, et al. "HIV Prevalence in the United States, 2000" Abstract 11. 9th CROI.

21. Neal JJ, Fleming PL. "Frequency and Predictors of Late HIV Diagnosis in the United States, 1994 through 1999" Abstract 474-M. 9th CROI.

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©1997,1998,1999,2000,2001,2002. The recently formed HIV Education Prison Project (HEPP) is a medical education program that targets a growing population, inmates in correctional facilities, that has been underserved in HIV care. It is part of the Brown University AIDS Program. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to heppnews@brown.edu. Website: HIV Education Prison Project.

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