Antiretroviral Therapy in HIV-infected Adults: Lipodystrophy and Metabolic Complications
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The lipodystrophy and metabolic complications that can arise during HAART have not been conclusively associated with one particular drug class or therapeutic agent, although some agents have been implicated more frequently. In fact, in July 2001, the FDA’s Division of Antiviral Drug Products wrote to all manufacturers of antiretroviral drugs and required that they include information on fat redistribution in their package inserts, a warning that had previously been reserved only for the PI class.
No official name or case definition currently describes the lipodystrophy or metabolic complications that occur in HIV-infected patients. Common HAART-associated body habitus changes include visceral fat accumulation in the abdomen, peripheral lipoatrophy, facial wasting, gynecomastia, and enlargement of the dorsocervical fat pad. Metabolic complications include hypercholesterolemia, hypertriglyceridemia, and insulin resistance.
Table 4 Overview of Antiretroviral Agents
| Drug | Dosage Form | Dosing Guidelines Food Effect | |||
| NRTIs | |||
| Zidovudine canadian (ZDV) (AZT, Retrovir drug, GlaxoSmithKline) | • 100-mg capsules
• 300-mg tablets • 10-mg/ml IV solution • 10-mg/ml oral solution |
300 mg b.i.d. or with 3TC as Combivir (300 mg ZDV/150 mg 3TC) b.i.d. or with 3TC + ABC as Trizivir (300 mg ZVD/150 mg 3TC/300 mg ABC) b.i.d. | Take without regard to meals |
| Didanosine generic (ddI)
(Videx®, Bristol-Myers Squibb Immunology) |
• 25-, 50-, 100-, 150- and 200-mg tablets
• 125-, 200-, 250- and 400-mg delayed-release capsules • 100-, 167-, and 250-mg sachets • Four- and eight-ounce glass bottles containing 2 or 4 g of ddI |
Tablets and capsules:
> 60 kg: 200 mg b.i.d. (preferred) or 400 mg q.d. (alternative)* < 60 kg: 125 mg b.i.d. (preferred) or 250 mg q.d. (alternative)* |
Levels decrease 55%; take one-half hour before or two hours after a meal |
| Zalcitabine (ddC) (HIVID®, Roche) | 0.375- and 0.75-mg tablets | 0.75 mg t.i.d. | Take without regard to meals |
| Stavudine (d4T) (Zerit canadian, Bristol-Myers Squibb Immunology) | • 15-, 20-, 30-, and 40-mg
capsules • 1-mg/ml oral solution |
> 60 kg: 40 mg b.i.d.
< 60 kg: 30 mg b.i.d. |
Take without regard to meals |
| Lamivudine (3TC) (Epivir generic,
GlaxoSmithKline) |
• 150-mg tablets
• 300-mg tablets • 10-mg/ml oral solution |
150 mg b.i.d. or with ZDV as Combivir b.i.d. or with ZDV+ ABC as Tizivir b.i.d. or 300 mg q.d. | Take without regard to meals |
| Abacavir (ABC) (Ziagen drug, GlaxoSmithKline) | • 300-mg tablets
• 20-mg/ml oral solution |
300 mg b.i.d. or with ZDV + 3TC as Trizivir b.i.d. | Take without regard to meals |
| NNRTIs | |||
| Nevirapine (NVP)
(Viramune®, Boehringer Ingelheim) |
• 200-mg tablets
• 10-mg/ml suspension |
200 mg daily for 14 days to lessen
the frequency of rash, then 200 mg b.i.d. |
Take without regard to meals |
| Delavirdine (DLV)
(Rescriptor®, Pharmacia & Upjohn, Agouron) |
• 100-mg capsules | 400 mg t.i.d. | Take without regard to meals |
| Efavirenz tablet (EFV)
(Sustiva®, Bristol-Myers Squibb Virology) |
• 50-, 100-, and 200-mg capsules
• 600-mg tablets |
600 mg qhs | May be taken with or without food, but patients should avoid taking immediately after a high-fat meal because absorption may increase
by 50% |
| PIs | |||
| generic Indinavir sulfate (IND) (Crixivan®, Merck) | • 200- and 400-mg capsulesf | 800 mg q8h or 800 mg with 100 mg to 200 mg of RTV b.i.d.; separate dosing with ddI by one hour | Levels decrease by 77% when taken after a high-fat meal; take one hour before or two hours after meals; may take with skim milk or low-fat meal
Indinivar sulfate (IDV)/ritonavir drug (RTV) combination may be taken without regard to meals |
| Drug | Dosage Form | Dosing Guidelines | Food Effect |
| PIs (continued) | |||
| Ritonavir (RTV) (Novir®, Abbott) | • 100-mg capsules
• 600-mg/7.5-ml oral solution |
600 mg q12h; also used at lower doses in combination with other PIs; separate dosing with ddI by two hours | Taking with food increases levels by 15%; take with food if possible; food may also improve tolerability |
| Saquinavir mesylate-HGC
(SQV-HGC) (Fortovase®, Roche) |
• 200-mg hard-gel capsules | 400 mg b.i.d. with RTV, not as a single agent ф | May be taken without regard to meals when taken with ritonavir (RTV) |
| Saquinavir mesylate-SGC
(SQV-SGC) (Fortovase®, Roche |
• 200-mg soft-gel capsules | 1,200 mg t.i.d. | Food increases levels six-fold; take with a large meal |
| Nelfinavir (NFV)
(Viracept generic, Agouron) |
• 250-mg tablets
• 50-mg/g oral powder* |
750 mg t.i.d. or 1,250 mg b.i.d. | Take with food |
| Amprenavir (AMP) (Agenerase®, GlaxoSmithKline) | • 50- and 150-mg capsules
• 15-mg/ml oral solution |
Capsules: 1,200 mg b.i.d. or 1,200 mg with
RTV 200 mg q.d.; or 600 mg with RTV 100 mg b.i.d. Oral solution: 1,400 mg b.i.d. (oral solution should only be used when capsules are not an option§) |
May be taken with or without food, but not recommended with a high-fat meal |
| Lopinavir/ritonavir
(LPV/RTV) (Kaletra®, Abbott) |
• Co-formulation of 133.3 mg LPV +33.3 mg RTV in a soft-gel capsule
• 80 mg LPV + 20 mg RTV/ml oral solution |
400/100 mg LPV/RTV (three capsules or 5 ml) b.i.d. | Take with food |
In a study of 1,077 patients from the HIV Outpatient Study (HOPS), hypercholesterolemia (above 240 mg/dl) was seen in 21.3% of patients and a high triglyceride level (above 400) was found in 20.7%; both of these laboratory values were elevated in 9% of patients. Controlling for age, increased cholesterol was associated with the use of ritonavir (RTV) (Novir®, Abbott) (P = .01) or generic lamivudine (3TC) (Epivir canadian, GlaxoSmithKline) (P = .033). A logistic regression model showed that elevated triglycerides were associated with any use of RTV, saquinavir (SQV) (Fortovase®, Roche) or stavudine (d4T) (Zerit®, Bristol-Myers Squibb) (P = .01). Only hypertriglyceridemia was associated with changes in body habitus (P = .01). Preliminary guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy are available, and further information about managing lipodystrophy and metabolic complications should be consulted.
Individual Classes and Agents
In conjunction with the growth in complexity of HIV therapy has been an expansion in the number of agents available to treat the disease. Until October 26, 2001, the most recent agents to be approved have all been within the three previously existing classes of antiretrovirals: the NRTIs, NNRTIs, and PIs. However, the recent approval of tenofovir has added a fourth class of agents, the NtRTIs. Table 4 summarizes the classes of existing antiretrovirals.
Cost and Cost-Effectiveness
The HIV Cost and Services Utilization Study interviewed a random sample of 2,864 patients who represented all American adults receiving care for HIV infection in 1996. The patients were observed for 36 months. The adjusted total per-patient expenditure in 1996 was $20,300, which fell 10°% to 18,300 in 1998 as a result of increased use of HAART. The estimated total costs of care to the patients in 1996 ranged from $6.7 to $7.8 billion.5,123 Although overall expenditures declined by 16% and expenditures for hospital care declined 43% between 1996 and 1998, pharmaceutical expenditures increased by 33%.5 Table 5 shows the 2002 comparative monthly costs of therapy per month for individual agents in the three drug classes. This study showed that although there was a large decline in expenditures for hospital care for these patients, there was only a modest decline in overall costs.
Table 5 Comparative Costs of Antiretroviral Agents*
|
Monthly |
|
| Oral Drug | Cost |
| NRTIs | |
| Generic Abacavir (Ziagen®) 300 mg b.i.d. |
$407.70 |
| Zidovudine (Retrovir®) 300 mg b.i.d. |
$354.50 |
| Lamivudine drug (Epivir®) I50 mg b.i.d. |
$303.40 |
| Lamivudine/zidovudine (Combivir®) | |
| (300 mg AZT/150 mg 3TC) b.i.d. |
$657.86 |
| Didanosine (Videx drug) 200 mg b.i.d. |
$266.26 |
| Didanosine EC (Videx® delayed-release) | |
| 400 mg 1 q.d.f |
$30I.79 |
| Stavudine drug (Zerit®) 40 mg b.i.d. |
$334.89 |
| Trizivir (300 mg AZT/150 mg | |
| 3TC/300 mg abacavir) b.i.d. |
$I,065.56 |
| Zalcitabine (HMD®) 0.75 mg t.i.d. |
$273.05 |
| Tenofovir (Viread®) 300 mg q.d. |
$408.00 |
| NNRTIs | |
| Nevirapine (Viramune®) 200 mg b.i.d. |
$336.08 |
| Delavirdine (Rescriptor®) 400 mg t.i.d. |
$3I6.35 |
| Efavirenz (Sustiva®) 600 mg q.d. |
$43I.65 |
| PIs | |
| Indinavir (Crixivan medication) 800 mg q8h |
$546.38 |
| Ritonavir (Novir®) 600 mg b.i.d. |
$77I.54 |
| Indinavir (Crixivan®) 800 mg b.i.d. | |
| + ritonavir (Novir®) I00 mg b.i.d. |
$492.84 |
| Saquinavir-SGC (Fortovase®) 1,200 mg t.i.d. |
$720.96 |
| Nelfinavir (Viracept®) I,250 mg b.i.d. |
$756.66 |
| Amprenavir (Agenerase®) I,200 mg b.i.d. |
$706.I2 |
| Amprenavir (Agenerase®) 600 mg | |
| + ritonavir (Novir®) I00 mg b.i.d. |
$48I.65 |
| Lopinavir/ritonavir (Kaletra®) 400 mg/ | |
| 100 mg b.i.d. |
$703.50 |
A study from the Department of Veterans Affairs (VA) exemplifies the cost shifting that has occurred as a result of increased HAART utilization. The VA is the largest single provider of HIV services in the U.S. More than 17,000 veterans received HIV services during 1997, including 1,172,565 outpatient visits (for pharmacy visits and the cost of drugs) and 170,579 hospital days. Comparison data from 1996 and 1997 showed a 38% increase in outpatient visits. At the same time, there was a 37% decline in hospital admissions and a 41% decrease in total days spent in the hospital. This shift from inpatient to outpatient visits resulted in an estimated net savings of $18 million in 1997 alone. Further, Gebo et al. concluded that in their patient population, a PI-containing regimen significantly decreased the costs of hospitalization and the treatment of opportunistic infections. Despite increases in drug expenditures, total health care costs were stable or slightly lower for these patients.
A computer-based simulation model, which used the CD4 cell count and viral load measurements, was developed to evaluate the cost-effectiveness of HAART for HIV infection. Data from the AIDS Clinical Trials Group 320 study; the Johns Hopkins HIV Clinic cohort study; the Italy, Netherlands, Canada, and Australia Study (INCAS); and the Sustiva canadian-006 trial were used. This study, conducted from a societal perspective, included all costs and health effects in the model. The outcomes included primary and recurrent opportunistic infections, life expectancy, and life expectancy adjusted for quality of life and lifetime costs.
It was found that a three-drug HAART regimen increased the projected quality-adjusted life expectancy by 1.38 to 2.67 years, with cost-effectiveness ratios ranging from $13,000 to $23,000 per quality-adjusted year of life gained, compared with the absence of any therapy. The HAART regimen appears to be a cost-effective use of resources.
Future Directions
The complexity of multidrug regimens, serious toxicities, and viral resistance to therapy are compelling reasons to continue to improve the existing options for HIV treatment. New formulations of drugs under development include sustained-release formulations of zidovudine medication (ZDV) (Retrovir®, GlaxoSmithKline) and stavudine (d4T) (Zerit®, Bristol-Myers Squibb) to decrease dosing frequency; a higher-dose version of delavirdine (DLV) (Rescriptor®, Agouron/Pharmacia & Upjohn) (200 mg); and to reduce pill burden, 800-mg saquinavir (SQV) hard-gel capsules (HGC) (Fortovase®, Roche) for co-administration with ritonavir (RTV) Novir®, Abbott) and fosamprenavir (GW-433908), a pro-drug of amprenavir (AMP) (Agenerase®, GlaxoSmithKline).
Enfuviritide (Fuzeon™, Roche), a member of a new class of drugs known as fusion inhibitors, was approved in March 2003. This is the fifth drug class to be added to the anti-retroviral armamentarium. Some other drugs still under investigation are listed in Table 6.
Table 6 Selected Antiretrovirals Under Development
| Drug Class Development Phase | |
| NRTIs | |
| ACH-126,443 | II |
| SPD-754 | II |
| Amdoxovir | I/II |
| Emtricitabine (Emtriva™) | Approved (2003) |
| NNRTIs | |
| Calanolide A | I/II |
| Capravirine | II/III |
| DPC-083 | II |
| DPC-A78277 | Preclinical |
| Protease Inhibitors | |
| AG-7088 | II |
| BMS-234475/CGP-6I755 | II |
| DPC-684 | I |
| Tipranavir | III |
| Fosamprenavir | New Drug |
| Application filed | |
| Atazanavir (Reyata) | Approved (2003) |
| R-944 | I |
| VX-385 | I |
| Attachment Inhibitors | |
| PRO-542 | Preclinical |
| Co-receptor Antagonists | |
| SCH-C | I |
| SCH-D | Preclinical |
| Fusion Inhibitors | |
| R-724 (T-I249) | II |
| Integrase Inhibitors | |
| GW-8I078I (S-1360) | II |
| Naphtyridine carboxamide | I
_____ |
The FDA approved emtricitabine (Emtriva™, Gilead), an NRTI for the treatment of HIV infection in adults in combination with other antiretroviral medications, in July 2003. The indication was based on analyses of both treatment-naive and treatment-experienced HIV patients with virological suppression on an HIV treatment regimen in controlled studies of 48 weeks’ duration. Emtricitabine has potent in vivo antiretroviral activity and can be given once daily. In previous studies, its antiretroviral efficacy and safety were comparable to those of twice-daily 3TC.
The future success of agents under development is contingent upon their ability to ease administration, to reduce toxi-city, and to maintain potency against resistant mutant viral species.
For the past few years, limiting drug exposure has been an area of considerable investigation. Broadly defined, these strategies fall under the umbrella of structured treatment interruption (STI), or the planned interruption of therapy by discontinuation of all antiretroviral agents. This approach is being considered in four potential settings:
1. a “drug holiday” to provide the patient time without the burden and potential toxicity of therapy and to improve the response to therapy in heavily pretreated patients, if possible, by allowing re-emergence of wild-type virus
official canadian pharmacy
2. strategic discontinuation during the first trimester of preg-nancy
3. “reimmunizing” the patient to HIV to regain immunological control via regeneration of an HIV-specific immune response
4. “structured intermittent therapy” to reduce overall exposure to antiretroviral therapy, a method often taken to reduce toxicity and cost and to improve the patient’s quality of life
The utility of STI must be evaluated further before its potential role in therapy can be fully elucidated.
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