More? HIV Medicine 2007, Chapter 5.12: Download

HIV Medicine
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There is no question about it: a lot of money is made from ART and the market has strong competition. One example is the price politics of the firm Abbott over Norvir™. When the sales figures of the competitor PI Reyataz™ (which needs Norvir™ as a booster) threatened to come close to those of the Abbott flagship Kaletra™, withdrawal of Norvir™ tablets from the market was seriously considered. Only after public demonstrations was it retained with a 400 % price increase… Despite all criticism and discussion of costs, two things should not be forgotten: firstly the enormous costs of developing new drugs, which can sometimes amount to a billion dollars or more. By far the majority of new substances never reach the market. It is even questionable whether even a licensed drug such as T-20 will recuperate the development costs. According to Roche, the development cost 600 million dollars. In order to cover these high production costs, many thousands of patients worldwide would have to be treated with T-20 over several years - an unrealistic scenario. Secondly, US estimates assume an expenditure of between $13,000 and $23,000 per additional QUALY (quality-adjusted year of life; Freedberg 2001) which is cheap in comparison to many other therapies. HAART reduces the cost of treatment of opportunistic infections, inpatient and outpatient care. In the Hannover cohort, between 1997 and 2001, total annual outgoings per patient decreased from 35,865 Euro to 24,482 Euro (Stoll 2002). Many patients are able to work again, resulting in an overall economic gain for society (Sendi 1999). Nevertheless, the fact remains, that HAART is expensive. It is important that initially only one packet is prescribed, even if the standard dose of Retrovir™ 250 mg it is still just enough for 20 days - almost 20 years after its introduction! In this way, one avoids sitting on a mountain of pills if intolerability occurs. Prescription of more than three months supply of medication should also be avoided. Due to the payment obligation for each packet, many patients refuse it anyway. In the future, it will certainly become more and more important to be informed about the costs of HAART. Prevention The following discusses the preventative effect of HAART on the AIDS epidemic as well as other medical prevention strategies with the exclusion of the ABC (abstinence, be faithful, condom use) rule that is propagated by governments. HAART - makes an exceptionally important contribution to prevention, which is usually underestimated (Hosseinipour 2002). The lower the viral load, the lower the infectivity. A prospective study of 415 HIV-discordant couples in Uganda showed that of 90 new infections over a period of 30 months, none occurred from an infected partner with a viral load below 1,500 copies/ml. The risk of infection increased with every log by a factor of 2.45 (Quinn 2000). In a study from Thailand on 493 patients, this factor was 1.81. Not one single case of infection was observed below 1,094 copies/ml (Tovanabutra 2002). In the San Francisco Cohort, infectiousness in the HAART era dropped by 60 %, based on the probability of transmission per couple (Porco 2004); a study from Spain on heterosexual pairs calculated as much as 80 % (Castilla 2005). Most patients are interested in knowing: "Do I still need to use a condom?" The answer is: "Yes" Studies have shown that the decrease of viral load in plasma and seminal fluid is roughly parallel and that a decrease of several logs in plasma after several months may also be seen in semen (Liuzzi 1999). Although the same seems to be true for the vaginal and anorectal mucosa, individual risk remains difficult to estimate (Cu-Uvin 2000). Furthermore, viral load levels in blood and other body fluids do not always correlate with one another. Safe sex is still advisable, even if both partners are infected. HIV-infected patients are not protected from superinfections with new viral strains; and infections with several subtypes are often associated with accelerated disease progression (Gottlieb 2004). Transmission of resistant strains is also possible (Yang 2005). There has also been concern that the preventive effects of HAART lead to an increase in risk behavior. Calculations have shown that an increase in risk behavior of only 10 % would offset the effects of HAART (Blower 2001, Law 2001). However, one meta-analysis concluded that HAART does not increase risk behavior of patients, even if viral load is undetectable (Crepaz 2004). The gladly circulated scenario of the irresponsible HIV patient, who sets his desires loose again in the age of HAART, putting innocent people at risk, is just a rumor. On the other hand, with the decreasing interest in AIDS in the media and politics, a reduced awareness of the risks have been observed. In the French PRIMO Cohort, so-called risk contacts of patients increased from 5 to 21 % between 1998 and 2001 (Desquilbet 2002). In 2005, the number of new infections in homosexual men in Germany rose by 20 %- an all time high! Small syphilis endemics among HIV-infected individuals are being reported in every major city in the US and Europe. Of equal concern is the data on transmission of multiresistant viruses. A case, such as that of the New York patient, who became infected with a multidrug-resistant virus and underwent rapid progression within a few months (Markowitz 2005), showed how important protection and "safer sex" remains. Circumcision - circumcision of the male foreskin reduces the risk of infection from diverse sources through unprotected intercourse (overview: Weiss 2006). This is probably also true for HIV (Siegfried 2006). A randomized controlled study on 3,274 men in South Africa produced a notable result (Auvert 2005). After 18 months of observation, 20 infections occurred in the circumcision group 0.85 infections in 100 person years), in contrast to 49 in the control group (2.1/100). This corresponded to a reduction in the transmission risk of 61 %. Likewise, in a large randomized study in Uganda on 4,966 men, the risk of infection with HIV decreased from 1.33 to 0.66/100 person years (Gray 2007). This effect is explained by the presence in the male foreskin of CD4-positive Langerhans cells, which act as the primary target cell for the HIV infection. It has been estimated that in Africa alone circumcision could prevent approximately 2 million HIV infections in the next few years (Williams 2006). However, the results of these pilot studies need to be confirmed, as some questions still remain open. Sexual behavior following circumcision, surgical complications, ethical and logistical problems are just a few aspects (Lie 2006). Further large, randomized studies are currently underway. It is also clear that circumcision is no substitute for safe sex - the risk is still there. Microbicides are chemical substances, which are usually applied topically as vaginal gels, in order to kill or immobilize HIV and other germs. Currently, very heterogeneous mechanisms are being investigated. These include inactivated substances, which disrupt the viral structures, as well as those which bind to the target cell and inhibit them or antiretroviral drugs such as tenofovir or the nucleoside analog stampidine (overview: Stone 2006). Ideally, microbicides would also be active against sexually transmitted diseases, as these significantly increase the risk of HIV transmission (Schwebke 2005). It should not be forgotten that so far, no microbicide has demonstrated a protective effect in clinical studies. In addition, investigations crop up every so often, in which the HIV-transmission risk increases on a microbicide, as for example with nonoxynol-9 (Van Damme 2002). In January 2007, there was once again a serious setback. In a randomized study of the Contraceptive Research and Development Program (CONRAD), a non-profit-making research organization, 1,333 women in South Africa, Benin, and Uganda received either a placebo preparation or a microbicide of cellulose sulfate gel. This locally applied gel (UshercellÔ) from Polydex, Toronto, proved to be very promising in earlier studies (El-Sadr 2006). However, an interim analysis of CONRAD showed that the users of the cellulose sulfate gel had an increased risk of HIV transmission, and the study was prematurely stopped (http://www.conrad.org). Although the reasons for the increased risk are still unclear, another trial on cellulose sulfate in Nigeria was also terminated. It is questionable whether there is really a future for microbicides after these sobering results. Methodical and ethical problems of randomized studies make the development of effective microbicides very difficult. PREP (pre-exposure prophylaxis) - includes the prophylactic administration of antiretroviral drugs. PREP approaches in high-risk groups (in particular prostitutes) has mainly been with tenofovir, or sometimes with tenofovir and emtricitabine. However, these studies are not without criticism. Under pressure from activists and diverse organizations, a trial sponsored by NIH and the Gates Foundation was stopped in 2004; and the same happened in 2005 in Cameroon and Nigeria (Cohen 2004, Sing 2005). Usually, the investigators and pharmaceutical firms are accused of neglecting the informed consent to the study and of allowing infected patients to go without medical treatment. Unexplained long-term side effects, interactions, possible resistances and an increased pressure on prostitutes to dispense with condoms - the ethical and political problems of PREP approaches are considerable. However, in view of the catastrophic number of new infections worldwide, they remain an approach which is worth further investigation. At the World AIDS Conference in Toronto, the results of a large PREP trial were first released (Petersen 2006). Approximately 1,200 women with a high HIV risk, in Ghana, Nigeria, and Cameroon, received either placebo or tenofovir daily. After one year, 6 versus 2 seroconversions were noted. Although this difference was not significant, the safety of PREP could at least be demonstrated. Currently, several placebo-controlled CDC studies are underway in the USA, Botswana, and Thailand. Adherence Adherence is the Achilles heel of antiretroviral therapy. Non-adherence is one the most important factors in treatment failure (review: Turner 2002). Insufficient plasma drug levels and partial suppression of viral load are the conditions under which resistance can develop. There is no question that HAART has to be taken regularly. All or nothing: with regard to resistance, it is still better not to take any drugs at all. Taking more than 90 % or less than 69 % of drugs were both associated with a lower risk for resistance (Sethi 2003). Compliance is defined as consent and acceptance of a treatment regimen by the patient. In the mid-90s a newer, more politically correct term was adopted - "adherence". This term describes both clinician and patient working together to achieve a treatment concept acceptable for both, and emphasizes, that not only the patient may be responsible for treatment failure. Adherence includes all factors that influence staying on a regimen, in terms of "acceptability". Whichever term is used, three facts remain: 1. If only 95 % of pills are taken, treatment success is put at risk. 2. Clinicians usually overestimate the compliance of their patients. 3. The more complex the therapy, the worse the compliance. "Risk patients" for non-compliance include individuals with substance or alcohol abuse or those experiencing side effects. Many studies have, however, also identified patients with depression, living alone, or of a younger age, as being particularly at risk (Murri 2001, Frank 2002, Glass 2006). Positive factors are physician experience, confidence of the patient in the positive effects of HAART, and social support. Race, sex or stage of disease does not seem to be relevant. The individual's view of disease and health, acceptance of modern medicine and fear of side effects are further considerations. However, all of these factors vary greatly, and in the end, compliance is difficult to predict in individual cases (Lerner 1998). Experience and intuition of the healthcare professionals are required. The importance of taking drugs regularly has been demonstrated in numerous studies. In one study of 99 patients, in which compliance was evaluated by way of an electronic monitoring system, the rate of treatment failure was only 22 % in patients with a level of compliance of at least 95 % (95 % of doses taken). Failure rates in patients with 80-94 % or < 80 % compliance were 61 % and 80 %, respectively (Paterson 2000). However, it must be taken into consideration that this much cited study is now relatively old. Newer drugs with longer half-lives, higher resistance barriers and better overall pharmacokinetics may be more forgiving of noncompliance. In the aforementioned study, with regard to compliance, 41 % of patients were misjudged by their treating clinicians. Nurses seemed to have a better understanding of their patients, judging incorrectly in only 30 % of cases (Paterson 2000). In other studies, too, compliance tends to be overestimated (Miller 2002). The importance of compliance is also demonstrated by the successes reported in patients with directly observed therapy (DOT). In Florida's correctional facilities 100 % of participants in a DOT study had a viral load below 400 copies/ml at 48 weeks, compared with 81 % in an unmonitored control group in the general population (Fischl 2001). Poor adherence not only leads to virological failure. It also has immunological consequences. In an analysis of two prospective studies, patients with a compliance of 100 %, 80-99 % and 0-79 % experienced reductions in viral load of 2.77, 2.33 and 0.67 logs after one year. At the same time, the CD4 cell count rose by 179, 159 and 53 cells/µl, respectively (Mannheimer 2002). Furthermore, non-compliance also has clinical effects beyond the surrogate markers. In a Spanish study, patients who did not take more than 10 % of their drugs had a four-fold increase in mortality risk (Garcia 2002). This data has been confirmed in other studies (Maher 1999, Hogg 2000, Wood 2004). Hospital stays are also less frequent in patients with high compliance (Paterson 2000). In addition, it should be considered that noncompliant patients increase the risk of transmission of resistant viruses. The basic mechanisms for development of resistance should be explained to patients. One must emphasize that, in contrast with other chronic illnesses, resistance mutations do not disappear once they have developed. Diabetes and hypertension make effective examples: whereas these diseases may "tolerate" forgetting the occasional tablet (blood glucose or blood pressure levels can easily be lowered again the next day), HIV is different. Even short-term lapses can have irreversible consequences. And every new occurrence of resistance makes therapy more complicated and more difficult. Patients have to be made aware of this unusual feature of HIV disease. These conversations should be repeated from time to time and become a standard component of routine care. Cooperation with special treatment discussion groups offered by various support organizations can be useful. The table below provides additional suggestions. In addition, very different strategies have been investigated in order to improve compliance. They range from the employment of additional nurses to telephoning patients regularly. A large recent ACTG study showed that at least the regular telephone reminders do not appear to have any influence on compliance (Collier 2005). In contrast, the cooperation with special therapy consultations, such as those offered by some AIDS-help groups has proven itself. Twelve steps to improve adherence 1. Every patient should receive a written (legible!) treatment plan, which should be reviewed at the end of the visit. The plan should include a telephone number to call in case of problems or questions. 2. Patient and clinician should agree on the treatment plan. The patient's concerns or critical questions should be discussed. 3. The patient should have the impression that the treatment regimen was not randomly chosen, but tailored to his/her individual needs. 4. The explanation of a new or modified treatment plan takes time, and should not be rushed - all questions should be answered. 5. The reasons why adherence is so important should be explained. It makes sense to repeat such conversations - they should not only take place when initiating or modifying treatment, but should be part of routine care. 6. Possible side effects should be explained, as well as what can be done to alleviate them. 7. Support groups and other types of assistance should be utilized and offered. 8. It is important to tell the patient to come back if any problems are encountered with HAART - it is better to solve them together than have the patient try to deal with them alone at home. 9. The patient should know that the treatment regimen must be taken in its entirety ("Last month I left out the big tablets"). 10. Prescriptions should be documented, in order to get a rough idea of adherence. Irregularities should be addressed openly. 11. During the early phases of therapy, the patient should be informed of treatment success as seen by reduction of viral load and rise in CD4 count. 12. Ensure clinical vigilance to detect the early signs of depression and treat appropriately. If compliance remains low Despite all efforts, some patients will not be able to improve their compliance. Physicians and other healthcare providers are advised not to take this personally or to feel offended should a patient not want to participate in the advances of medicine. Although it may be difficult to accept others' views on life, disease and treatment, tolerance and acceptance should remain fundamental to the interactions of all healthcare providers with their patients. Some providers, especially those who treat selective patient populations in university settings, sometimes forget the reality of routine medical practice. Upholding the principles of modern medicine usually doesn't help here, and putting patients under pressure achieves even less. It is important to clearly outline and explain one's own position. The question of whether noncompliant patients should continue to be treated with antiretroviral therapy is not always easy to address. On the one hand, there are patients who benefit even from suboptimal therapy; on the other hand, drugs are expensive and should not be prescribed readily. If poor compliance is suspected in the initial consultation, restraint should be applied. One also needs to be aware of criminal intentions - there have repeatedly been reports of patients who have done deals with pharmacists (black sheep occur everywhere!) for other medication (methadone, etc.) or money. Therefore, written prescriptions should be endorsed where possible. If in doubt about the compliance or honesty of the patient, plasma levels can be measured (preferably without prior warning). The Duesberg sect The patients that refuse antiviral treatment on principal are a special case. These patients are often treated by (shockingly misdirected) doctors, who call themselves "Duesbergians" (after the US virologist and AIDS dissident Peter Duesberg, who denied any association between AIDS and illness). For healthcare providers, it can be very difficult to watch patients go to their fate with open eyes, without doing anything. Informative consultations should be as detailed as possible and documented in writing. Below is an actual example: An approximately 40-year-old patient with a long history of untreated HIV, 30 CD4 cells/µl and cerebral toxoplasmosis, which improved significantly after 4 weeks of acute treatment (the last MRI still showed scattered lesions) presented at the HIV outpatients department. Clinically, he was relatively well and fully oriented, and due for discharge that day. In a conversation, the patient categorically refused to start the urgently recommended antiretroviral therapy ("one can die from AZT, and the other drugs are not much better") as well as antibiotics. Therefore he could also not continue to take the toxoplasmosis maintenance therapy, which had caused him from the first day in hospital to suffer from diarrhea (NB, perhaps cryptosporidiosis), skin problems (seborrheic dermatitis, thrush), and an extreme loss of weight (MAC?). It was most important for him to have a break from everything. In cases such as these, we make sure the patients sign the information sheets. Every patient is allowed to and should decide for himself (if fully oriented) - but he must know and be fully informed about what he is doing. It is important to give the patient control: if he changes his mind (and of course, if the toxoplasmosis relapses), he can return! Arguing with medical Duesbergians does not achieve anything in our experience. The view of the world that this sect has is closed. A discussion about the prayer-wheel-like repeated old arguments just uses up time and wastes energy. Fortunately, these cases have become less common. The initial widespread skepticism about HAART has decreased significantly, due to its overwhelming success in the last few years. And: where Peter Duesberg is concerned (thankfully), it has also become quieter, at least as far as his HIV activities goes. The sect is in decline. References of Costs, Prevention, Compliance 1. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005; 2: 298. http://amedeo.com/lit.php?id=16231970 2. Blower SM, Aschenbach AN, Gershengorn HB, Kahn JO. Predicting the unpredictable: transmission of drug-resistant HIV. Nat Med 2001, 7:1016-20. http://amedeo.com/lit.php?id=11533704 3. 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