Cost-effectiveness of chemoprophylaxis after occupational exposure to HIV

OBJECTIVES: To assess the economic efficiency of recent US Public Health Service recommendations for chemoprophylaxis with a combination of antiretroviral drugs following high-risk occupational exposure to human immunodeficiency virus (HIV). To provide a framework for evaluating the relative effectiveness and costs associated with candidate postexposure prophylaxis (PEP) regimens. METHODS: Standard techniques of cost-effectiveness and cost-utility analysis were used. The analysis compares the costs and consequences of a hypothetical, voluntary combination-drug PEP program consisting of counseling for all HIV-exposed health care workers, followed by chemoprophylaxis for those who elect it vs an alternative in which PEP is not offered. A societal perspective was adopted and a 5% discount rate was used. Hospital costs of recommended treatment regimens (zidovudine alone or in combination with lamivudine and indinavir) were used, following the dosing schedules recommended by the US Public Health Service. Estimates of lifetime treatment costs for HIV and acquired immunodeficiency syndrome were obtained from the literature. Because the effectiveness of combination PEP has not been established, the effectiveness of zidovudine PEP was used in the base-case analyses. MAIN OUTCOME MEASURES: Net PEP program costs, number of HIV infections averted, cost per HIV infection averted, and cost-utility ratio (net cost per discounted quality-adjusted life-year saved) for zidovudine, lamivudine, and indinavir combination PEP. Lower bounds on the effectiveness required for combination regimens to be considered incrementally cost saving, relative to zidovudine PEP alone, were calculated. Multiple sensitivity and threshold analyses were performed to assess the impact of uncertainty in key parameters. RESULTS: Under base-case assumptions, the net cost of a combination PEP program for a hypothetical cohort of 10,000 HIV-exposed health care workers is about $4.8 million. Nearly 18 HIV infections are prevented. The net cost per averted infection is just less than $400,000, which exceeds estimated lifetime HIV and acquired immunodeficiency syndrome treatment costs. Although combination PEP is not cost saving, the cost-utility ratio (about $37,000 per quality-adjusted life-year in the base case) is within the range conventionally considered cost-effective, provided that chemoprophylaxis is delivered in accordance with Public Health Service guidelines. Small incremental improvements in the effectiveness of PEP are associated with large overall societal savings. CONCLUSIONS: Under most reasonable assumptions, chemoprophylaxis with zidovudine, lamivudine, and indinavir following moderate- to high-risk occupational exposures is cost-effective for society. If combination PEP is minimally more effective than zidovudine PEP, then the added expense of including lamivudine and indinavir in the drug regimen is clearly justified.     

Bronchopulmonary carcinosarcoma

Recent evidence demonstrating the efficacy of zidovudine, as well as experience with protease inhibitors, led to revision of recommendations for occupational exposures to human immunodeficiency virus-infected blood. At our hospital, this resulted in significant increases in rates of reported exposures and prophylaxis initiation. Among 10 healthcare workers given three-drug, protease-inhibitor-containing regimens, five completed 4 weeks, two completed 4 weeks of two drugs, and three stopped due to intolerance. Three workers missed work due to side effects.     

Increasing levels of leukocyte-derived inflammatory mediators in plasma and cAMP in platelets during follow-up after acute cerebral ischemia

PURPOSE: The author reviews the risks of occupational exposure to HIV and provides a rationale for new postexposure guidelines for healthcare workers. OVERVIEW: Approximately 50,000 percutaneous exposures occur yearly among healthcare workers in the United States. Of these, approximately 5000 involve exposures to blood that is known to be infected with HIV. The risk of transmission after percutaneous exposure to HIV-tainted blood has been estimated to be 0.3%, but the risk may be considerably higher to the healthcare worker if any of the following is present: a deep injury; visible blood on the sharp device; a procedure that involves a needle placed in the patient's artery or vein; and a patient with advanced AIDS. The increasing resistance of HIV strains to antiretroviral therapy continues to make treatment more difficult. CLINICAL IMPLICATIONS: Postexposure prophylaxis with zidovudine may reduce the risk of occupational infection by 80%. Advances in the ability to ameliorate HIV transmission rates and to treat individuals with resistant disease through innovations in drug therapy, engineering of controls for injury prevention, and more focused postexposure evaluation offer the hope of reducing this infrequent, but dangerous, occupational threat.     

Treatment response and durability of a double protease inhibitor therapy with saquinavir and ritonavir in an observational cohort of HIV-1-infected individuals

OBJECTIVE: To evaluate treatment response, durability and tolerance of a four-drug regimen including saquinavir and ritonavir in combination with either zidovudine/lamivudine or stavudine/lamivudine. DESIGN: Observational cohort of HIV-positive individuals. METHODS: Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1-3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures. RESULTS: A group of 56 male patients were included and followed for 48 weeks. Of these, 66% had already taken a protease inhibitor. Viral load dropped by a median 1.98 log10 HIV RNA copies/ml from baseline (interquartile range: 1.49-2.46) and became undetectable (< 400 copies/ml) in 68% of patients. Response varied: 9% were non-responders (HIV RNA reduction < 0.5 log10 copies/ml) and 23% were incomplete responders (nadir of HIV RNA > 400 copies/ml). After 48 weeks, viral load remained undetectable in 49%. Median CD4+ T lymphocyte count increased from 191 x 10(6) to 418 x 10(6) cells/l (range, 241-537 x 10(6) cells/l). Although protease inhibitor and nucleoside pretreatment selected for drug-resistant viral mutants, only the protease inhibitor experience was identified as a risk factor for therapeutic failure. Adverse events occurred in 73% of patients and led to a change of therapy in 9%. CONCLUSION: Despite advanced HIV disease and pretreatment with multiple antiretroviral drugs, a strong initial treatment response to this drug regimen was observed. However, virological failure occurred in 51% of patients after 48 weeks and frequent adverse events complicated therapy.     

Prophylaxis after occupational exposure to human immunodeficiency virus (HIV)

Reasons for seeking consultation among health care workers due to potential or supposed risk of HIV infection were analyzed. From August 1990 till July 1996 41 health care providers were consulted including: 22 nurses, 1 student of nursing college, 3 midwives, 4 laboratory workers and 7 physicians (surgeons and gynaecologist). Type of exposure to HIV and applying of safety precautions were evaluated in each case. In 10 cases the offer of postexposure prophylaxis with zidovudine was accepted (6 nurses, 1 student of nursing college, 3 surgeons). Exposure to HIV was described as: needlestick immediately after it was used in a HIV/AIDS patient, injury with a surgical needle while operating on an HIV infected blood. In the remaining cases the fear of HIV infection was due to work without protective gloves (nurses, laboratory workers), performing surgery on HIV (+) patient, (surgeons, nurses) or short-time contact of HIV infected blood with undamaged skin (nurses). Following conclusions can be drawn from our study: 1. Health care workers undertake safety precautions only when they are informed about HIV seropositivity of the patient. 2. Patients whose HIV serologic status is not known are considered not to create health risk for medical staff. 3. The level of knowledge of health care workers about risk of acquiring HIV infection, lack of risk and ways of diminishing the risk is poor. 4. None of followed health care workers was HIV-seropositive after occupational exposure to HIV.     

Hepatitis, HIV, and the dermatologist: a risk review

The practice of dermatology has always carried with it the risk of patient-acquired infection. This review covers health risks associated with the care of HIV-infected patients and patients who are chronic carriers of hepatitis B or C virus, protection options to reduce exposure, and protocols should exposure occur. Hepatitis B continues to be a major risk to health care workers, killing approximately 200 per year. In contrast, as of 1990, only 327 total health care personnel had acquired HIV, with no deaths reported. Data are lacking regarding hepatitis C, but it appears to be an increasing concern. Needlesticks are the most common form of occupational transmission, with an infectivity rate of 30% for hepatitis B, 3% for hepatitis C, and 0.3% for HIV. Universal precautions are the cornerstones of safety. Hepatitis B vaccination, zidovudine prophylaxis, and hepatitis C therapy are discussed as postexposure recommendations are reviewed.     

Acute generalized exanthematous pustulosis: a cutaneous adverse effect due to prophylactic antiviral therapy with protease inhibitor

We describe a human immunodeficiency virus-seronegative man who presented with a skin disorder that we diagnosed as acute generalized exanthematous pustulosis, which we believe was an adverse reaction to combination prophylactic therapy with zidovudine, lamivudine, and protease inhibitor for human immunodeficiency virus. Cutaneous adverse effects are rarely reported with the use of these antiviral drugs.     

Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring

The safety, pharmacokinetics, and antiretroviral activity of lamivudine alone and in combination with zidovudine was studied in pregnant women infected with human immunodeficiency virus type 1 (HIV-1) and their neonates. Women received the drugs orally from week 38 of pregnancy to 1 week after delivery. Neonate therapy began 12 h after delivery and continued for 1 week. Both treatment regimens were well-tolerated in women and newborns. Lamivudine and zidovudine pharmacokinetics in pregnant women were similar to those in nonpregnant adults. Lamivudine and zidovudine freely crossed the placenta and were secreted in breast milk. Neonatal lamivudine clearance was about half that in pediatric patients; zidovudine clearance was consistent with previous reports. HIV-1 RNA could be quantified in 17 of the 20 women. At the onset of labor/delivery, mean virus load had decreased by approximately 1.5 log10 copies/mL in both treatment cohorts. Although not definitive for HIV-1 infection status, all neonates had HIV-1 RNA levels below the limit of quantification at birth and at ages 1 and 2 weeks.     

A new mechanism in serine proteases catalysis exhibited by dipeptidyl peptidase IV (DP IV)--Results of PM3 semiempirical thermodynamic studies supported by experimental results

There has been considerable interest and controversy over the potential clinical role of combination antiretroviral therapy, primarily in the treatment of patients with established HIV infection. In order to model the hematologic toxicity of high-dose combination antiretroviral therapy, the HL60 myeloid leukemia cell line was exposed to zidovudine, dideoxycytidine and/or didanosine. The results suggest that the myelotoxicity of high-dose combination antiretroviral therapy may be controlled by using very brief periods of drug exposure. Brief intense antiretroviral therapy may offer a useful approach, particularly in the treatment of patients with AIDS-related neoplasms who are also receiving myelotoxic antineoplastic drugs.     

Initial multicenter experience with double nucleoside therapy for human immunodeficiency virus infection during pregnancy

OBJECTIVE: To study maternal and neonatal effects of combination nucleoside analog therapy administered to human immunodeficiency virus (HIV)-infected pregnant women for maternal indications. METHODS: A multicenter, prospective observational study was undertaken at six perinatal centers in the United States and Canada that supported regional referral programs for the treatment of HIV-infected pregnant women. Demographic, laboratory, and pregnancy outcome data were collected for 39 women whose antiretroviral treatment regimens were expanded to include more than one nucleoside analog for maternal indications. The 40 newborns were monitored at pediatric referral centers through at least three months of age to ascertain their HIV infection status. RESULTS: For all 39 women, zidovudine (ZDV) therapy was instituted at 13.4 +/- 8.2 weeks, with a second agent (lamivudine [3TC] in 85% of cases) being added at a mean gestational age of 17.6 weeks. Duration of therapy with two agents was 20.6 +/- 10.4 weeks overall, with no women stopping medications because of side effects or toxicity. No significant changes in maternal laboratory values were seen, except for an increase in mean corpuscular volume, over the course of pregnancy. No clinically significant adverse neonatal outcomes were noted, with all but the three preterm newborns leaving hospital with their mothers. Neonatal anemia (hematocrit < 50%) was seen in 62% of newborns, with no children needing transfusion; mild elevations of liver function tests, primarily aspartate aminotransferase, were noted in 58% of newborns tested, though none were clinically jaundiced. Overall rate of neonatal HIV infection was 2.5% (95% confidence interval: 0.1-13.2%). CONCLUSION: Combination antiretroviral therapy during pregnancy with two nucleoside analogs was well-tolerated by mothers and newborns, with no significant short-term toxicities or side effects noted. Surveillance of exposed newborns' hematologic and liver function appears warranted.     

Cost-effectiveness of post-exposure prophylaxis following sexual exposure to HIV

OBJECTIVES: To assess the cost-effectiveness, relative to other health-related interventions in the U.S., of post-exposure prophylaxis (PEP) following potential HIV exposure through sexual contact with a partner who may or may not be infected, and to compare the relative cost-effectiveness of dual- and triple-combination PEP. METHODS: Standard techniques of cost-utility analysis were used to assess the cost-effectiveness of PEP with a four-week regimen of zidovudine and lamivudine, or zidovudine, lamivudine, and indinavir. Due to a lack of empirical data on the effectiveness of PEP with combination drug regimens, the analysis assumed that combination PEP was no more effective than PEP with zidovudine alone. The main outcome variable is the cost per quality-adjusted life year (QALY) saved by the program. RESULTS: Providing PEP to a cohort of 10,000 patients who report receptive anal intercourse with a partner of unknown HIV status (who is assumed to be infected with probability equal to 0.18) would prevent about 20 infections, at an average net cost of about US$ 70,000 per infection averted. The cost-utility ratio, US$ 6316 per QALY saved, indicates that PEP is highly cost-effective in this instance. Moreover, triple-combination PEP would need to be about 9% more effective than dual-combination PEP for the addition of indinavir to the regimen to be considered cost-effective. Prophylaxis following receptive vaginal exposure is cost-effective only when it is nearly certain that the partner is infected; PEP for insertive anal and vaginal intercourse does not appear to be cost-effective. CONCLUSIONS: From a purely economic standpoint, PEP should be restricted to partners of infected persons (e.g., serodiscordant couples), to patients reporting unprotected receptive anal intercourse (including condom breakage), and possibly to cases where there is a substantial likelihood that the partner is infected. Providing PEP to all who request it does not appear to be an economically efficient use of limited HIV prevention and treatment resources.     

Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations

Since its introduction in 1987, zidovudine monotherapy has been the treatment of choice for patients with HIV infection. Unfortunately it has been established that the beneficial effects of zidovudine are not sustained due to the development of resistant viral strains. This has led to the strategy of combination therapy, and in 1995 treatment with zidovudine plus didanosine, or zidovudine plus zalcitabine, was demonstrated to be more effective than zidovudine monotherapy in preventing disease progression and reducing mortality in patients with HIV disease. Recent work demonstrates an even greater antiviral effect from triple therapy with 2 nucleosides, zidovudine plus zalcitabine with the addition of saquinavir, a new protease inhibitor drug. The HIV protease enzyme is responsible for the post-translational processing of gag and gag-pol polyprotein precursors, and its inhibition by drugs such as saquinavir, ritonavir, indinavir and VX-478 results in the production of non-infectious virions. As resistance may also develop to the protease inhibitors they may be used in combination, and future strategies may well include quadruple therapy with 2 nucleoside analogues plus 2 protease inhibitors. Administration of protease inhibitors alone or in combination with other drugs does raise a number of important pharmacokinetic issues for patients with HIV disease. Some protease inhibitors (e.g. saquinavir) have kinetic profiles characterised by reduced absorption and a high first pass effect, resulting in poor bioavailability which may be improved by administrating with food. Physiological factors including achlorhydria, malabsorption and hepatic dysfunction may influence the bioavailability of protease inhibitors in HIV disease. Protease inhibitors are very highly bound to plasma proteins (> 98%), predominantly to alpha 1-acid glycoprotein. This may influence their antiviral activity in vitro and may also predispose to plasma protein displacement interactions. Such interactions are usually only of clinical relevance if the metabolism of the displaced drug is also inhibited. This is precisely the situation likely to pertain to the protease inhibitors, as ritonavir may displace other protease inhibitor drugs, such as saquinavir, from plasma proteins and inhibit their metabolism. Protease inhibitors are extensively metabolised by the cytochrome P450 (CYP) enzymes present in the liver and small intestine. In vitro studies suggest that the most influential CYP isoenzyme involved in the metabolism of the protease inhibitors is CYP3A, with the isoforms CYP2C9 and CYP2D6 also contributing. Ritonavir has an elimination half-life (t1/2 beta) of 3 hours, indinavir 2 hours and saquinavir between 7 and 12 hours. Renal elimination is not significant, with less than 5% of ritonavir and saquinavir excreted in the unchanged form. As patients with HIV disease are likely to be taking multiple prolonged drug regimens this may lead to drug interactions as a result of enzyme induction or inhibition. Recognised enzyme inducers of CYP3A, which are likely to be prescribed for patients with HIV disease, include rifampicin (rifampin) [treatment of pulmonary tuberculosis], rifabutin (treatment and prophylaxis of Mycobacterium avium complex), phenobarbital (phenobarbitone), phenytoin and carbamazepine (treatment of seizures secondary to cerebral toxoplasmosis or cerebral lymphoma). These drugs may reduce the plasma concentrations of the protease inhibitors and reduce their antiviral efficacy. If coadministered drugs are substrates for a common CYP enzyme, the elimination of one or both drugs may be impaired. Drugs which are metabolised by CYP3A and are likely to be used in the treatment of patients with HIV disease include the azole antifungals, macrolide antibiotics and dapsone; therefore, protease inhibitors may interact with these drugs. (ABSTRACT TRUNCATED)     

Current treatment of HIV infection

The treatment of HIV infection in the industrialised countries has undergone manifest changes during the past decade. Since the advent of zidovudine in 1987, the first agent capable of delaying disease progression, several other nucleoside analogues have been introduced, though in retrospect the effect of these drugs can now be seen to have been moderate. With the introduction of proteinase inhibitors, more effective control of infection became possible, and the combination of a proteinase inhibitor with two nucleoside analogues yielded a triple-drug treatment capable of halting progression for a large proportion of patients. Thus, during recent years the disease course has changed in character from successive deterioration of the immune defence system to a condition where most patients can live virtually normal lives in many respects. For some patients, however, the new drugs have been associated with side effects, and our knowledge of the long-term effects is still insufficient.     

Advanced HIV infection treated with zidovudine monotherapy: lifetime values of absolute cost-effectiveness as a pharmacoeconomic reference for future studies evaluating antiretroviral combination treatments. The Osservatorio SIFO sui Farmaci

OBJECTIVE: This study was undertaken to evaluate the cost and the effectiveness of zidovudine monotherapy in patients with advanced HIV infection and to derive preliminary data on the cost-effectiveness of the triple treatment with saquinavir plus zalcitabine plus zidovudine compared with zidovudine alone. DESIGN: We used a combined method of survival analysis utilizing both the quality-adjusted time without symptoms or toxicity (Q-TWIST) method and the Gompertz approach. This combined method was applied to assess the absolute cost-effectiveness and cost-utility ratios of zidovudine monotherapy and to perform a preliminary incremental cost-effectiveness comparison of saquinavir plus zalcitabine plus zidovudine versus zidovudine alone. The clinical material used in our study was derived from two reports on the treatment of advanced HIV infection. Data of lifetime costs of HIV infection were obtained from published information. RESULTS: In patients with advanced HIV infection treated with zidovudine monotherapy, lifetime survival was 252.1 discounted person-years per 100 patients. Using an average lifetime cost of $93,000 (discounted) per individual, the absolute ratio of cost-effectiveness for zidovudine monotherapy was $36,980 per life-year, while the absolute cost-utility ratio was $47,112 per quality-adjusted life-year. In the comparative analysis of saquinavir plus zalcitabine plus zidovudine versus zidovudine alone, our calculations showed that the administration of the triple treatment can have an "average" cost-effectiveness, provided that mean lifetime survival per patient (discounted) is improved to at least 3.68 years (with an average survival gain of at least 14 mo per patient). CONCLUSIONS: The values of absolute cost-effectiveness and cost-utility ratios for zidovudine monotherapy are a useful reference point for further pharmacoeconomic studies in the area of antiretroviral drugs.     

Antiretroviral drugs as a public health intervention for pregnant HIV-infected women in rural South Africa: an issue of cost-effectiveness and capacity

OBJECTIVE: To estimate cost-effectiveness and capacity requirements for providing antiretroviral drugs to pregnant HIV-infected women in rural South Africa. SETTING: Hlabisa health district, where HIV prevalence among pregnant women was 26.0% in 1997. METHODS: Calculation of the number of paediatric HIV infections averted under three scenarios, and their cost. No intervention was compared with scenario A (zidovudine delivered within current infrastructure), scenario B (zidovudine delivered through enhanced infrastructure), and scenario C (short-course zidovudine plus lamivudine delivered through enhanced infrastructure). Cost-effectiveness was defined as cost per infection averted and cost per potential life-year gained. Capacity was determined in terms of staff and infrastructure required to effectively implement the scenarios. RESULTS: With no intervention, 657 paediatric HIV infections were projected for 1997. In scenario A this could be reduced by 15% at a cost of US$ 574 825, in scenario B by 42% at US$ 1520770, and in scenario C by 47% at US$ 764901. In scenario C, drugs accounted for 76% of costs, whereas additional staff accounted for 18%. Cost per infection averted was US$ 2492 and cost per potential life-year gained (discounted at 3%) was US$ 88. Cost of scenario C was equivalent to 14% of the 1997 district health budget. At least 12 extra counsellors and nurses and one laboratory technician, together with substantial logistical and managerial support, would be needed to deliver an effective intervention. CONCLUSION: Although antiretrovirals may be relatively cost-effective in this setting, the budget required is currently unaffordable. Developing the capacity required to deliver the intervention would pose both a major challenge, and an opportunity, to improve health services.     

Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus

BACKGROUND: The Pediatric AIDS Clinical Trials Group Protocol 076 reported a reduction in the rate of perinatal transmission of the human immunodeficiency virus (HIV) from 25.5 percent to 8.3 percent with a three-part regimen of zidovudine given ante partum, intra partum, and to the newborn. We examined the effects of abbreviated zidovudine regimens on perinatal HIV transmission using data from the HIV polymerase-chain-reaction (PCR) testing service of the New York State Department of Health. Pregnant women who received abbreviated regimens rather than the recommended regimens did so because of limited prenatal care or by choice. METHODS: The requisition form used by the PCR testing service included information on the demographic characteristics of the infants and the timing of any perinatal treatment with zidovudine. We also analyzed data on the timing of zidovudine prophylaxis collected by chart review in a subgroup of 454 infants as a means of validating the results in the entire cohort. RESULTS: From August 1, 1995, through January 31, 1997, specimens from 939 HIV-exposed infants who were 180 days of age or younger were submitted for PCR testing. The rates of perinatal HIV transmission varied depending on when zidovudine prophylaxis was begun. When treatment was begun in the prenatal period, the rate of HIV transmission was 6.1 percent (95 percent confidence interval, 4.1 to 8.9 percent); when begun intra partum, the rate was 10.0 percent (3.3 to 21.8 percent); when begun within the first 48 hours of life, the rate was 9.3 percent (4.1 to 17.5 percent); and when begun on day 3 of life or later, the rate was 18.4 percent (7.7 to 34.3 percent). In the absence of zidovudine prophylaxis, the rate of HIV transmission was 26.6 percent (21.1 to 32.7 percent). CONCLUSIONS: These results confirm the efficacy of zidovudine prophylaxis and suggest that there are reductions in the rates of perinatal transmission of HIV even with the use of abbreviated regimens that are begun intra partum or in the first 48 hours of life.