Current concepts in antiretroviral therapy failure

Currently, the goal for the first and second, possibly the third, antiretroviral regimen is the suppression of HIV replication to plasma levels below assay detection (ie, <50 HIV-1 RNA copies/mL). In patients with advanced treatment failure and resistance to numerous drugs, the goal of therapy has been to reduce viral load as much as possible and to maintain immunologic and clinical integrity. With the recent availability of new drugs and new classes of drugs, complete suppression of viral replication may be possible even in late salvage. When designing a regimen for a patient for whom antiretroviral therapy has failed, the regimen should contain at least 3 active drugs, and regimens are best selected with assistance from genotypic and phenotypic drug resistance testing. The selection should also be guided by knowledge of potential pharmacokinetic interactions among drugs. This article summarizes a presentation on antiretroviral failure by Carlos del Rio, MD, at the 8th Annual clinical meeting for Ryan White CARE Act clinicians in New Orleans in June 2005, sponsored by the International AIDS Society-USA and includes more recent data presented at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in 2006.     

Paediatric use of second-line anti-tuberculosis agents: a review

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.     

The new drugs and how to use them

More antiretroviral drugs are becoming available, increasing potential treatment regimens but also increasing the complexity of HIV treatment. The 4 newest of the 15 available antiretroviral agents are described: efavirenz (Sustiva, EFV), abacavir (Ziagen, ABC), adefovir (Preveon, ADV), and amprenavir (Agenerase, APV). Information on dosing, side effects, and interactions with other drugs is provided.     

Antiretroviral therapy for drug users

Injection drug use represents the primary risk factor for up to 40% of patients with HIV infection. Physicians are generally reluctant to prescribe antiretroviral therapy (ART) for these patients due to possible poor adherence, and the potential for complex drug interactions to occur. Providing daily observed ART in conjunction with methadone maintenance therapy (MMT) has significantly improved accessibility of ART for many drug users. Knowledge of potential drug interactions between methadone, ART, and both legally and illegally prescribed drugs has permitted such interactions to be anticipated and either avoided or treated appropriately. Optimizing ART for drug users therefore demands a multidisciplinary approach from medical, clinical pharmacology and psychiatric services.     

Examining the production costs of antiretroviral drugs

OBJECTIVES: To present direct manufacturing costs and price calculations of individual antiretroviral drugs, enabling those responsible for their procurement to have a better understanding of the cost structure of their production, and to indicate the prices at which these antiretroviral drugs could be offered in developing country markets. METHODS: Direct manufacturing costs and factory prices for selected first and second-line antiretroviral drugs were calculated based on cost structure data from a state-owned company in Brazil. Prices for the active pharmaceutical ingredients (API) were taken from a recent survey by the World Health Organization (WHO). The calculated prices for antiretroviral drugs are compared with quoted prices offered by privately-owned, for-profit manufacturers. RESULTS: The API represents the largest component of direct manufacturing costs (55-99%), while other inputs, such as salaries, equipment costs, and scale of production, have a minimal impact. The calculated prices for most of the antiretroviral drugs studied fall within the lower quartile of the range of quoted prices in developing country markets. The exceptions are those drugs, primarily for second-line therapy, for which the API is either under patent, in short supply, or in limited use in developing countries (e.g. abacavir, lopinavir/ritonavir, nelfinavir, saquinavir). CONCLUSION: The availability of data on the cost of antiretroviral drug production and calculation of factory prices under a sustainable business model provide benchmarks that bulk purchasers of antiretroviral drugs could use to negotiate lower prices. While truly significant price decreases for antiretroviral drugs will depend largely on the future evolution of API prices, the present study demonstrates that for several antiretroviral drugs price reduction is currently possible. Whether or not these reductions materialize will depend on the magnitude of indirect cost and profit added by each supplier over the direct production costs. The ability to achieve price reductions in line with production costs will have critical implications for sustainable treatment for HIV/AIDS in the developing world.     

Drug interactions between antineoplastic and antiretroviral therapies: Implications and management for clinical practice

Despite the impact of combined antiretroviral therapy (cART) on human immunodeficiency virus (HIV)-related mortality, malignancies remain the second most common cause of death in HIV infection in developed countries. In addition to the AIDS-defining malignancies, other cancers such as Hodgkin's lymphoma and anal cancer, are more frequent in HIV-infected patients who survive longer even though they do not have complete immune restoration The use of concomitant antineoplastic chemotherapy and cART have been demonstrated to be feasible and effective in patients with HIV-related malignancies; however, many drugs used in cART regimens have the potential for causing drug interactions as a result of their ability to either inhibit or induce the cytochrome P450 (CYP) enzyme system. Since many antineoplastic drugs are also metabolised by the CYP system, co-administration with cART could result in either drug accumulation and possible toxicity, or rapid drug metabolism and decreased efficacy. Unfortunately, very limited prospective interaction data are available to safely guide the combined use of cART and chemotherapy. This paper reviews the potential drug interactions and therapeutic considerations of the antiretroviral agents used to treat HIV and the most common anticancer agents used in the treatment of malignancies found in patients with HIV infection.     

Rapid progression of atherosclerotic coronary artery disease in patients with human immunodeficiency virus infection

We describe the case of a 39-year-old human immunodeficiency virus (HIV)-infected man with angiographically documented rapid progression of coronary artery disease. Over a time course of only 2 months, he developed high-grade stenosis of the left anterior descending coronary artery. The risk of myocardial infarction is increased in patients with HIV infection receiving antiretroviral therapy. However, the absolute risk is small and the marked overall benefits of antiretroviral therapy are evident. Patients receiving HIV protease inhibitors should be screened for hyperlipidemia, hyperglycemia, and hypertension. They may be candidates for lipid-lowering therapies depending on their long-term prognosis and individual risk of cardiovascular disease. Care is need because of possible drug interactions between lipid-lowering drugs and antiretroviral therapy. Invasive treatment of acute myocardial infarction does not differ from that in patients not infected with HIV. The rate of progression of coronary artery disease and the restenosis rate, however, are often unexpectedly high in these patients.     

Appearance-related side effects of HIV-1 treatment

In the early years of the AIDS epidemic, HIV infection was associated with visible signs and symptoms, adding to the stigma associated with the disease. Physical manifestations associated with HIV infection included muscle wasting, lymphadenopathy, Kaposi's sarcoma, candidiasis, molluscum contagiosum, and hairy leukoplakia. With the advent of antiretroviral therapy, particularly the introduction of highly active antiretroviral therapy in 1996, many of these outward manifestations of the disease became rare. Ironically, however, the treatments used to control HIV infection (and its visible markers) have themselves been associated with appearance-related side effects. Patients may develop changes in fat distribution, rashes, skin hyperpigmentation, or paronychia. These effects not only have cosmetic and psychological consequences but also may decrease adherence to therapy, potentially causing regimen failure and drug resistance. Newer antiretroviral agents offer improved potency, more convenient dosing, and more treatment options with the potential for fewer side effects and drug interactions, which should foster optimal adherence by the patient. However, these newer drugs are also associated with appearance-related side effects, which must be considered in the selection of treatment regimens. This paper reviews the appearance-related side effects associated with classes of antiretroviral drugs as well as individual agents, including the newer antiretrovirals.     

The reasoning behind decisions not to take up antiretroviral therapy in Australians infected with HIV

A substantial minority of HIV-infected Australians are not taking antiretroviral drugs. This study investigated the reasons behind their decision not to do so. Anyone who was HIV-infected but not taking antiretroviral drugs could participate. A self-administered, anonymous questionnaire was used, the principal recruitment method being through insertion of the questionnaire into gay community newspapers in Sydney and Melbourne. All respondents were asked questions covering demographics, previous AIDS-defining illnesses, T-cell and viral load monitoring, and previous use of antiretroviral drugs. In addition, respondents who had considered going on antiretroviral treatment, but then decided not to do so, were given a list of possible reasons for their decision and asked to indicate how much each played a role in their thinking. Of the 270 respondents, the great majority were gay men. One-eighth had experienced AIDS-defining illnesses. Two-thirds had recently had T-cell and viral load tests. One-third had taken antiretroviral drugs previously. Over two-thirds had considered antiretroviral therapy, most having given the matter quite some thought. Reasons for not taking up therapy did not differ greatly at different stages of HIV disease. The most common individual reason was fear of side effects. Important themes that emerged from factor analysis of the reasons data included distrust of conventional medical approaches to treatment, practical problems associated with taking antiretroviral drugs, unpleasant thoughts that being on therapy would evoke, and acceptance of the idea of dying. The findings can be used by doctors and counsellors to help patients clarify and evaluate their concerns about antiretroviral therapy.     

Dyslipidemia and its Treatment in HIV Infection

HIV-infected patients have metabolic abnormalities that put them at increased risk of cardiovascular disease (CVD), including abnormalities associated with HIV infection itself, antiretroviral treatment, restoration to health, and body composition changes. The 2 major components of dyslipidemia in HIV-infected patients are hypertriglyceridemia and reduction in high-density lipoprotein (HDL) cholesterol (with likely altered function of HDL cholesterol); these abnormalities contribute to increased atherosclerotic risk. Adverse effects of antiretroviral drugs on lipids are not class specific but rather are associated with particular drugs. Thus, practitioners need to be cognizant of the risks of metabolic abnormalities posed by individual drugs. HIV infection increases CVD risk independent of the effects of traditional risk factors. The relative risk of CVD in HIV-infected patients has decreased in recent years with increasing use of lipid-lowering therapy. However, use of lipid-lowering therapy is complicated by numerous potential drug interactions with antiretroviral drugs that practitioners need to consider when prescribing lipid-lowering therapy. This article summarizes a presentation made by Carl Grunfeld, MD, PhD, at the International AIDS Society-USA continuing medical education program in Los Angeles in March 2010. The original presentation is available as a Webcast at www.iasusa.org.     

Inhaled corticosteroids in persons with HIV infection: not that harmless

There is a growing group of HIV-seropositive patients at risk for chronic lung disease due to their life style and age. The interaction between certain antiretroviral drugs and corticosteroid inhalation therapy is potentially dangerous but often unrecognised. We present three cases from our HIV-clinic of whom two developed full blown Cushing's syndrome over a short period of time and one presented with asymptomatic hypocortisolaemia due to serious drug interactions between HIV-drugs and inhaled corticosteroids. General practitioners, HIV and chest physicians should all be aware of this potentially life-threatening interaction and the combination of those products should be avoided where possible.     

Treatment of HIV infection in patients with comorbidity

HIV-positive patients often have concurrent diseases that may condition antiretroviral treatment. Changes may be due to interactions between medicines, specific toxicity of the antiretroviral treatment or malfunction of the diseased organ affecting the metabolism of the antiretrovirals.In cases of opportunist illness, Tuberculosis or Lymphoma/neoplasia of solid organ, certain points must be remembered. Only in case of severe immuno-depression will anti-Tuberculosis and anti-retroviral treatment be initiated simultaneously. If the CD4 figure is over 350, antiretroviral treatment must be postponed till after Tuberculosis. In case of Lymphoma or solid tumour, once the side-effects of chemotherapy after the first cycles are known, antiretroviral treatment will be started. The use of opiates counter-indicates the start of treatment because of lack of adherence, but can be given if the patient is taking methadone. Coinfection with the Hepatitis B or C virus will affect antiretroviral medication, depending on the degree of liver-cell failure and on how the Hepatitis is treated. Some change in the antiretroviral treatment may improve the metabolic disturbances or the appearance of the body. However, Hyperlactacidaemia requires modification or withdrawal of the nucleoside analogues. In case of renal failure only the drugs eliminated through this pathway need their dose adjusted so as to avoid the toxicity related to greater exposure to the drugs or their metabolites. Before a serious intercurrent picture, withdrawal of antiretroviral treatment for a limited period of times does not worsen the prognosis.     

Treatment of HIV-related tuberculosis—unresolved issues

Abstract:   Tuberculosis (TB) is one of the most common opportunistic infections among persons with HIV infection. However, there are uncertainties about both TB and HIV treatment regimens among patients with advanced immunodeficiency. On the TB treatment side, there are lingering concerns about whether patients with advanced immunodeficiency should have a more intensive regimen for TB treatment (longer duration, more frequent [daily] dosing and/or post-treatment isoniazid). The use of antiretroviral therapy among patients with TB and AIDS dramatically decreases the risk of death and other opportunistic infections. However, use of antiretroviral therapy during TB treatment is complicated by the need to coordinate the activities of the TB control program and the HIV care clinic, overlapping side-effect profiles of anti-TB and antiretroviral drugs, drug–drug interactions between the rifamycins and many antiretroviral drugs, and the occurrence of immune reconstitution inflammatory syndrome events. The combination of rifampin-based TB treatment and efavirenz-based antiretroviral therapy is clearly the best option for cotreatment of these two infections. However, there are a number of uncertainties about the optimal antiretroviral therapy if efavirenz cannot be used (because of intolerance, drug resistance, pregnancy or lack of an appropriate formulation in children). The competing risks of AIDS events and severe immune reconstitution inflammatory syndrome events raise uncertainties about the optimal timing of antiretroviral therapy during TB treatment. Despite all of these complexities, the treatment of HIV-related TB can be remarkably successful. I review these unresolved questions in the treatment of HIV-related TB and suggest studies to help resolve them.     

Sex differences in the pharmacologic effects of antiretroviral drugs: potential roles of drug transporters and phase 1 and 2 metabolizing enzymes

Sex differences in the pharmacologic effects of antiretroviral drugs are increasingly being reported. Emerging evidence suggests that women may be at increased risk of developing adverse effects of antiretroviral drugs. Several mechanisms have been proposed to explain sex differences in drug effects, including physiologic differences between men and women and the influence of sex hormones on drug metabolism. This article reviews sex-related variations in the levels of expression and activities of drug transporters and metabolizing enzymes involved in the disposition of the antiretroviral drugs, and postulates that these variations may partly explain sex differences in the responses to these drugs. Studies that explore relationships between levels of expression and activities of relevant enzymes and drug transporters and observed sex-related differences in treatment responses to antiretroviral drugs will help clarify the extent to which molecules involved in drug disposition affect sex differences in treatment response.     

Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition

The aim of this review is to discuss the effect of pharmacokinetic drug-drug interactions (DDIs) in the antiretroviral treatment of HIV infection. In particular, but not exclusively, DDIs due to the cytochrome P450 3A (CYP3A) inhibitor ritonavir, which is used to increase antiretroviral drug exposure - a technique known as pharmacokinetic enhancement or 'ritonavir boosting'- will be reviewed. The emphasis here will be on the treatment of important co-morbidities common in patients with HIV, including dyslipidaemia, hypertension, tuberculosis and opiate dependence, as well as on the potentially life-threatening interaction between ritonavir and inhalational steroids, and on the effect of acid-reducing agents on some antiretroviral drugs. Finally, further developments with regard to the use of CYP3A-blocking agents to augment the efficacy of antiviral therapy will be discussed.