Important note: Information in this article was accurate in February 2000. The state of the art may have changed since the publication date.
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Existing HIV treatment guidelines are updated every two years by the International AIDS Society1 and published in the Journal of the American Medical Association. Consensus from the Kaiser Foundation and Health and Human Services on new agents are inserted on the Guidelines Website as they become available (www.hivaits.org; last update 5/99).
A new version of the guidelines was recently published in the Journal of the American Medical Association.2 This article will review the new guidelines and highlight important changes since the last version was published 18 months ago (1998).
The July 1998 guidelines marked the codification of "highly active antiretroviral therapy" (HAART), a move that was supported by accumulating data from clinical and pathogenesis studies. At the time, there were a number of possible combination regimens available and an expanding number of choices for initial regimens.
In updates published since 1998, Efavirenz (Sustiva), Abacavir (Ziagen) and Amprenavir (Agenerase) have been added to the list of possible treatment options. Now a total of 15 antiretroviral agents are available in the United States (see Table 1). This underscores a guidelines recommendation that treatment of HIV-infected patients should be directed by a physician with extensive experience in the care of these patients.
The most significant difference between recommendations from 1998 and the "state of ART" in 2000 should come as no surprise to correctional HIV providers who have experience treating HIV patients. The concept that we should "hit hard, hit early" is evolving into "think hard, get the patient involved, then hit hard as early as possible." There are two reasons for the new hesitancy: (1) side effects and (2) adherence. Indeed, when the guidelines were written in 1998, protease inhibitors were having a miraculous effect on patients, and it appeared as if a cure for HIV was at hand. Since then, an array of side effects associated with HAART has been noted, and concerns about the long-term durability of the new drugs have been raised.
Correctional clinicians must carefully weigh the benefits of ART against the implications of long term therapy. For our patients who commonly experience destabilizing "life events," it becomes increasingly important to identify factors that can assist with stabilizing a patients' life before initiating treatment. Thus, rehabilitation, education, and careful discharge planning are increasingly important components of expert HIV management in corrections.
Initial theoretical modeling that HIV might be eradicated after about three years of complete viral suppression,3 have been withdrawn or radically amended, as reports of viral rebound after lengthy viral suppression accumulate.4 Unfortunately, the early speculative calculations did not take into account the existence of a small but critical pool of resting memory CD4+ lymphocytes that may contribute to persistence of replication-competent HIV in persons in spite of maximal viral suppression.5 6 7
The good news is that there are few reports of emergence of resistance when viral loads are suppressed to 20 to 50 copies/mL, even though most HIV researchers believe that viral replication is ongoing at low levels in reservoir sites. Furthermore, long-term suppression correlates with durability of virologic response to potent regimens.8 9 10
Even though patients are aware that close drug adherence is essential in preventing viral resistance, current regimens can be difficult for patients to adhere to. Recognizing this, the 1998 guidelines stated that adherence, short-term and long-term adverse effects, impact on quality of life, and evolution of resistance must be addressed with each person considering treatment. The 2000 guidelines discern advantages and disadvantages of each type of triple drug regimen, highlighting regimens that are easier to adhere to (see HIV 101, pg. 8).
Over the past few years, HIV care providers have been more concerned about the potential for long-term adverse drug effects. Lipodystrophy continues to be a significant side effect associated with protease inhibitors, and new studies appear to indicate that this condition may not be linked to any particular drug, rather it may be linked to the duration of therapy, to baseline body mass index, and to the quantity of fat in the patients' diet (for more on these recent findings, see next month's HEPP News for a report on the 7th Retrovirus conference). Reports of mitochondrial toxicity (manifested by fatigue, nausea, vomiting, abdominal pain, weight loss, dyspnea and low serum bicarbonate levels) have been associated with the use of NRTIs (particularly D4T and 3TC in one study of 106 cases by Boxwell and Styrt, who reported the FDA experience with mitochondrial toxicity at the 1999 ICAAC meeting, Abstract 1284). However, physicians who follow large numbers of incarcerated HIV-infected patients on HAART have failed to identify cases of severe mitochondrial toxicity to date, even though low serum "bicarbonate" is a frequent finding associated with treatment.
The last time the guidelines were published, there was growing recognition that early treatment initiation was associated with virologic, immunologic, and clinical benefits. Based on that perception, the International AIDS Society-USA panel recommends antiretroviral therapy for any patient with established HIV infection and a confirmed plasma HIV-1 RNA level 5,000-30,000 copies/mL or T-cell count 350-500 copies/µL who "is committed to the complex, long-term therapy" (see Table 2).
However, since the first therapeutic intervention (Plan A) is the one with the greatest chance of success, careful discussion of the regimen with the patient is recommended. The patient and physician should have another plan (Plan B) in mind for future treatment options, as well as some supplemental interventions (intensification) for the current regimen in case the initial regimen begins to falter.
In addition to drug failure secondary to poor adherence and suboptimal regimens, new data has accumulated over the past year that poor initial response may be due to pre-existing resistance to one or more of the selected agents.11 12 Genotyping at the time of treatment initiation is gaining favor (see section "Monitoring resistance" and Table 2, pg. 7).
Many would also consider therapy for patients who have detectable viral loads at any level and evidence of T-cell decline over time, however, there is a great deal of variation among experienced practitioners. (See HIV 101 pg. 8 for a discussion of the options available at the initiation of therapy.)
HHS/IAS guidelines (Table 2) currently recommend:
1. For asymptomatic patients with low plasma HIV RNA level (e.g., <5000/mL) and high CD4+ cell count (e.g., >350-500/µL) deferral of therapy with close follow-up may be recommended given treatment complexities, risk of adverse effects, consequences of resistance, and the possibility that such persons may fall into the category broadly described as long-term nonprogressor.
2. For those with moderately high HIV RNA levels (e.g., 5,000-30,000 copies/mL) and low CD4+ cell count (e.g. <350µL) therapy initiation is recommended, given independent prognostic significance of CD4+ cell count and clinical trial data support.corrections.
It is important to note that dual NRTI and dual PI regimens (without a third drug) are still not considered acceptable forms of ART. Dual NRTI regimens are not considered acceptable except when encountering patients currently succeeding on such a regimen. In those cases, most HIV practitioners would not "rock the boat" and would elect to keep the patient on the dual NRTI treatment.
An increasing concern has been whether disease stage should dictate the approach to treatment, since response rates decrease as HIV disease advances. Many experienced providers would consider using four drugs instead of three for patients who were starting therapy in later stage HIV/AIDS.
The most important factors to consider when first initiating a regimen include the following: (1) the patient's status (CD4+ T-cell count, viral load); (2) the potency of the regimen; and (3) the willingness and ability of the patient to adhere to the regimen. Additional considerations include the potential for drug interactions with other necessary medications, the potential for exacerbation of underlying medical conditions (e.g., neuropathy), the potential for long-term adverse effects, and the preservation of future treatment options. The latter point is worth keeping firmly in mind when discussing the initial regimen with the patient. A well-designed Plan A (initial regimen) keeps an equally effective and tolerable Plan B in reserve.
Beginning in 1998, the guidelines also featured a recommendation that quantitative viral load assays be used to monitor therapeutic response. The assays were considered "an essential parameter" by the 1998 guidelines panel and have become routine adjuncts to the HIV management portfolio, even in correctional settings. CD4+ T-cell counts have been de-emphasized as a result, and now should be followed at less frequent intervals (every three to six months) after the initiation of therapy.
A major advance in HIV treatment has been the development of plasma HIV RNA assays of increased sensitivity. These assays now achieve a range of about 20-50 to about 50,000 copies/mL of plasma. Most physicians obtain "Version 1" viral load measurements (sensitive to about 400 copies/mL) about six weeks to eight weeks after initiating therapy (sooner if failure is considered possible) as the first follow up indicator of response to a new regimen. If a response is seen, this is followed by an "ultrasensitive" assay about two to four weeks later. The expected response to an effective regimen is reduction of viral load by one log at eight weeks and no detectable virus at four to six months after initiation. The more rapid the reduction, the more effective the therapy is believed to be. The ultra sensitive assay confirms suppression of virus to the lowest detectable level and provides a benchmark for monitoring future response to therapy.
The rationale for tighter monitoring of viral loads is that evolution of resistance is restricted in patients who have viral load levels less than 50 copies/mL, even though low levels of viral replication probably still persist. Evidence of failing regimen includes: a decrease in CD4+ T-cell count of greater than 30% from baseline, and a greater than 0.5 log (or three-fold) increase in viral load. As intercurrent infections and vaccinations can affect viral loads, measurements should be repeated before instituting changes in therapy.
In 1998, both Genotyping and Therapeutic Drug Level monitoring were thought to be interesting but unproven; data now exists that these tools are useful in some clinical settings when implemented by fairly experienced HIV providers. Note that drug resistance testing is extremely costly. Resistance testing is best used in combination with a careful drug history to chose new regimens, since absence of genotypic or phenotypic evidence of resistance does not imply that a drug is guaranteed to be active. Drug level monitoring is available in some settings but will see limited use in correctional settings due to cost and the absence of good data showing better outcomes.
The strictest definition of treatment failure is that of confirmed detectable plasma HIV RNA (i.e., >50 copies/mL) in an adherent patient who had achieved a viral load level below the detection limit and has not experienced a recent acute infectious illness or vaccination. Indications for change include the following:
1. Less than a 0.5 to 0.75 log reduction of plasma HIV RNA by four weeks following initiation of therapy or less than a 1 log reduction at eight weeks (intensification might be the best option; see article by Rick Altice, MD in the October 1999 issue of HEPP News);
2. Failure to suppress plasma HIV RNA to undetectable levels within four to six months of initiating therapy (except when the patient starts from a very high e.g. 106 viral load).
3. Repeated detection of virus after initial suppression, suggesting viral resistance;
4. Any reproducible increase in the viral load defined as three fold or greater that is not due to acute intercurrent infectious illness or vaccination;
5. Dual nucleoside therapy (if viral load not undetectable). Note recommendation that all patients be on at least triple drug regimens, and note also that some clinicians would not "rock the boat" as discussed above;
6. Persistently declining CD4+ T-cell numbers as measured on at least two separate occasions;
7. Clinical deterioration (bearing in mind that some patients experience "reactivation" of opportunistic infection, or "immune reconstitution syndrome" as their immune system recovers with HAART).13 14
For patients with their second or third regimen failure, the decreasing number of options remaining for the patient may dictate a more conservative stance, with deferral of treatment changes until evidence of further increases in HIV RNA level or decreases in CD4+ T-cell count. Despite viral load increases, patients continue to benefit from potent regimens even after rebound viremia; for them, stopping therapy may result in further viral load increase, rendering re-establishment of adequate viral suppression more difficult.15
Sometimes patients exhibit a discordant CD4+ decline in the face of continued viral load suppression. In these cases, it is important to examine the regimen for evidence of myelotoxic drugs (AZT, Hydroxyurea) and to continue to monitor. The pathogenic causes for discordant responses are uncertain. For those with a confirmed CD4 cell decrease or confirmed rapid decrease, treatment changes may be useful.
"Induction/maintenance" regimens are not useful in the setting of HIV infection. Furthermore, studies of patients who have discontinued therapy after prolonged adherence to HAART and undetectable viral loads have now repeatedly shown viral rebound, in some cases to levels above the original set point.
The practice of adding to, or intensifying an existing regimen (reviewed by Dr. Rick Altice in the October 1999 issue of HEPP News) is a viable option in cases where the initial suppression of viral load after the initiation of therapy is less than adequate. For regimens achieving satisfactory early HIV RNA declines, but not below the limits of the most sensitive assay available, addition of drug(s) to intensify the regimen may maximize long-term treatment benefit. New drugs must be added before viral rebound occurs; otherwise, addition of a single new drug can be viewed as incremental therapy, which may promote resistance.
When the decision is made to change therapy, the approach should be guided by the reason for the change. For adverse effects, intolerance, or suboptimal adherence to an otherwise successful regimen (i.e., HIV RNA level below detection limits), selective substitution of individual, identifiable offending components is reasonable. When a change in therapy is indicated due to drug failure, the same principles and considerations apply as described previously. Efforts should be made to change the regimen in its entirety, using drugs with least potential for cross-resistance to current drugs. (See Table 4 in the 2000 guidelines). We will address this issue at greater length in a future issue of HEPP News.
New findings show that intermittent interruption of anti-retroviral therapy appears to have been beneficial. Some exposure to HIV primes the immune response and may, in the long run, be beneficial. Further studies 16 of intermittent interruption are underway. However, some researchers feel that there are other means of achieving immune stimulation in the absence of viral replication. Therapeutic vaccination is one such strategy (see HEPP News, March 2000, Retrovirus Conference update ).
While ART has been good news for patients and their providers, one area of concern for correctional budgeters has been the cost of long-term therapy. Over the past few years, researchers have published data that showed that the use of potent therapy has resulted in remarkable declines in hospitalization rates, morbidity, and mortality where the drugs are available.17 18 19 20 21 22 In community settings, protease inhibitor (PI)-containing regimens were shown to be cost-effective.23 24
Eradication of HIV with maximally suppressive therapy alone is unlikely given the present understanding of HIV pathogenesis; thus, therapy should be continued indefinitely. Even with virologic failure, many patients maintain clinical and immunologic benefit. 25 After attempts to adjust the drug regimen to suppress replication are made, therapy should be continued in the face of virologic failure, if evidence of clinical and immunologic stability exists. In contrast, stopping all antiretroviral therapy is reasonable when the patient, after discussion with the physician, still believes that the adverse effects outweigh potential benefits of therapy.
Primary infection, post exposure prophylaxis, and "Mega HAART" are also addressed by the 2000 guidelines, but will not be addressed here. (For more information see www.jama.org where the guidelines will be accessible until the end of March, 2000).
In short, HIV management has transformed dramatically over the past 20 years of the epidemic. We're now entering an age where we have many therapeutic options available to patients, and where careful choice, and even more careful adherence to a regimen, will determine the outcome of a disease that should, in most cases, resemble a chronic disease. See the March HEPP News for additional updates from the San Francisco Retrovirus meeting.
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* Consultant: Agouron Pharmaceuticals, Bristol-Myers Squibb Speaker’s Bureau: Agouron Pharmaceuticals, Bristol-Myers Squibb, Glaxo Wellcome
** Consultant: Agouron Pharmaceuticals, Bristol-Myers Squibb Speaker’s Bureau: Agouron Pharmaceuticals, Bristol-Myers Squibb
*** Speaker’s Bureau: Agouron Pharmaceuticals, Bristol-Myers Squibb, DuPont, Glaxo Wellcome, Merck, Roche
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3.Perelson AS, Essunger P, Cao Y, et al. "Decay characteristics of HIV-1-infected compartments during combination therapy." Nature. 1997 May 8;387(6629):188-91.
4.Ortiz G, Jin X, Markowitz M et al. "Containment of breakthrough HIV plasma viremia in the absence of antiretroviral drug therapy is associated with a broad and vigorous HIV specific cytotoxic T lymphocyte (CTL) response. " Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections Chicago, IL, Jan 31- Feb 4, 1999.Abstract 256.
5.Wong JK, et al. "Recovery of replication-competent HIV despite prolonged suppression of plasma viremia." Science 1997 Nov 14;278(5341):1291-5
6.Finzi D, Hermankova M, Pierson T, et al. "Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy." Science 1997 Nov 14;278(5341):1295-300.
7.Stuyver L, Mizell SB, et al. "Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy." Proc Natl Acad Sci U S A 1997 Nov 25;94(24):13193-7
8.Kempf DJ, Rode RA, Xu Y, et al. "The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir." AIDS 1998 Mar 26;12(5):F9-14
9.Montaner JS, DeMasi R, Hill AM. "The effects of lamivudine treatment on HIV-1 disease progression are highly correlated with plasma HIV-1 RNA and CD4 cell count." AIDS 1998 Mar 26;12(5):F23-8
10.Montaner J, Rae S, et al. In: Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept 28-Oct 1, 1997; Toronto, Ontario. Abstract A-14.
11.Little SJ, et al. "Reduced antiretroviral drug susceptibility among patients with primary HIV infection." JAMA 1999 Sep 22-29;282(12):1142-9
12.Boden D, et al. "HIV-1 drug resistance in newly infected individuals." " JAMA 1999 Sep 22-29;282(12):1135-41
13.Philips P, Zala C, Rouleau D, Montaner JSG. "Mycobacterial Lymphadenitis: Can Highly Active Antiretroviral Therapy (HAART) Unmask Subclinical Infection?" In: Program and Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections; Jan 22-26, 1997; Washington, DC. Abstract 620
14.Race EM, Adelson-Mitty J, et al. "Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease." Lancet 1998 Jan 24;351(9098):252-5
15.Kaufman D, Pantaleo G, Sudre P, Telenti A. "CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study." Lancet 1998 Mar 7;351(9104):723-4
16.Luzuriaga K. Keynote speech at the 6th Conference on Retroviruses and Opportunistic Infections, Chicago IL, Jan 31-Feb 3, 1999.
17.Palella FJ, Delaney KM, Moorman AC, et al. "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators." N Engl J Med 1998 Mar 26;338(13):853-60
18.Hogg RS, O'Shaughnessy MV, Gataric N, et al. "Decline in deaths from AIDS due to new antiretrovirals." Lancet 1997 May 3;349(9061):1294
19.Chiasson MA, Berenson L, Li W, et al. "Accelerating Decline in New York City AIDS Mortality." In: Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; Feb 1-5, 1998; Chicago, Ill. Abstract 9b, Session 6.
20.Reggy A, et al. "Protease Inhibitors and Declining AIDS Deaths in New York City (NYC)" In: Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; Feb1-5, 1998; Chicago, Ill. Abstract 771, Late Breaker 7.
21.Heath KV, Yip B, et al. "Improved survival among HIV-infected individuals following initiation of antiretroviral therapy." JAMA 1998 Feb 11;279(6):450-4
22.Katlama C, Valantin MA, Calvez V, et al. "ALTIS PLUS: Long-term D4T-3TC with and without Ritonavir" In: Program and abstracts of the 5th Conference on Retroviruses and Opportunistic Infections; Feb 1-5, 1998; Chicago, Ill. Abstract 376, Session 50.
23.Anis AH, Hogg RS, Yip B, et al. "Average annual drug cost and its determinants in a population based cohort of HIV-positive adult men and women." Pharmacoeconomics 1998 Mar;13(3):327-36
24.McCollum M, et al. "HAART Reduced Overall Costs of HIV Care at DVAMC-Denver" In: Program and abstracts of the 5th Conference on Conference on Retroviruses and Opportunistic Infections; February 1-5, 1998; Chicago, Ill. Abstract 200, Session 28.
25.Kaufman D, et al.
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©1997,1998,1999,2000. 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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