6.12. Prevention, compliance, costs

– Christian Hoffmann –

In the following, some aspects of antiretroviral therapy will be discussed in more detail that have only been mentioned briefly in previous chapters.

Prevention

About 30 years after AIDS was first described a prophylactic vaccination remains a distant prospect. In 2007 two highly promising vaccine studies were prematurely interrupted. It seems doubtful now that a vaccine to effectively prevent HIV infection will be discovered anytime soon – the moderate but surprisingly successful RV144 vaccine study will not change that (Rerks-Ngarm 2009, see chapter on Preventive Vaccination). Several experts believe that a promising vaccine candidate does not exist presently (Desrosiers 2008, Nathanson 2008) while others say it is time to get used to the fact that a vaccine may never come. Neither blind hope nor time schedules have proved very helpful. Some vaccine studies up until now can in fact be regarded as counter-productive, fatiguing both sponsors and the community.

Considering all this, prevention will continue to be the central means of controlling the HIV epidemic. However, common prevention strategies focused on the ABC guidelines (abstinence, be faithful, condom use) have reached their limits. In 2009 UNAIDS declared a worldwide increase of 2.2 million new infections. In every major city in the US or in Europe syphilis endemics in HIV-infected patients have been reported. In Germany, for example, the number of new infections among men who have sex with men (MSM) has been almost continuously rising since 2001.

It seems clear that advertisements and brochures alone are not the solution, especially when these simple publicity mechanisms are not maintained. High-risk groups are not being reached effectively. Prevention remains an arduous business and success is not immediately visible nor is it profitable. Sexual behavior is not easily modified by a few advertisements or brochures.

For some time, preventive medicine in HIV has been taking completely new and sometimes unusual paths to reach focus groups. Terms such as serosorting, seropositioning, dipping or strategic positioning show that the medical world is learning to face reality. People have sex and not everyone cares about, follows, or can follow guidelines. Recent studies with serosorting, choosing sexual partners according to perceived HIV serostatus, show that new prevention strategies can be developed (Morin 2008).

The following focuses mainly on medical prevention strategies. In 2010 there have been groundbreaking new findings in this area regarding PrEP and microbicides.

ART & Prevention

Antiretroviral therapy is an important contribution to prevention, possibly the most important (Hosseinipour 2002). As these studies show:

  • In a group of 415 HIV-discordant couples in Uganda 90 new infections were diagnosed over a period of 30 days. Not a single infection was caused by an infected partner with a viral load below 1500 copies/ml. With every additional log of HIV RNA, infection risk increased by a factor of 2.45 (Quinn 2000).
  • In a study in Thailand with 493 HIV-discordant couples, the factor was 1.81. No infection from a partner with less than 1094 copies/ml was recorded (Tovanabutra 2002).
  • In a study in Spain with 393 heterosexual HIV-discordant couples, a transmission rate of 8.6% was observed between 1991 and 2003. No infection was recorded with infected partners who were receiving combination ART.
  • In a group of 534 MSM in San Francisco, infectiousness based on the probability of transmission per couple decreased by 60% between 1994 and 1998 (Porco 2004). The HIV incidence decreased in spite of the reported higher number of partners and risk contacts, even though not all of the HIV-infected partners were on antiretroviral therapy.
  • In a Spanish study with 62 HIV-discordant couples (22 HIV-infected women, 40 HIV-infected men, all of them on ART), 76 “natural” pregnancies were diagnosed. Not a single HIV infection of a non-infected partner was recorded (Barreiro 2006).

The above-mentioned clinical studies show clearly that the lower the viral load in the plasma, the less infectious the patient. In an ongoing meta-analysis in 11 cohorts with 5021 heterosexual couples (and 461 HIV transmissions) the transmission rate of patients on ART was 0.46 per 100 person years (5 cases). Not one transmission was detected from anyone who was below 400 copies/ml (Attia 2009).

Test and treat?

At the end of 2008 a statistical paper caused great discussion. A research group led by the Director of WHO Kevin De Cock calculated how to, at least theoretically, curtail and even eliminate the worldwide HIV epidemic (Granich 2008). For this ambitious goal they concentrated totally on the preventive effect of antiretroviral therapies. They compared the common treatment strategy used today, beginning ART only on symptomatic patients or on those who have less than a certain number of CD4 T cells, to a theoretical strategy that seems simple enough. Every person is tested for HIV once a year and if found positive, starts ART immediately, irrespective of CD4 T cells or viral load. The study was based on population data in South Africa, where 17% of the adult population is HIV-infected and on data from a successful intervention in Malawi. Other preconditions of the calculation model are that infectiousness of treated versus not-treated patients was estimated at 1%. The case-reproduction number, the so called R0 number of new infections caused by one infection, was crucial for this calculation. The corresponding simple assumption that R0 of <1 is required in order to reduce the incidence and to eventually eliminate HIV means that an incidence rate of less than one new case per 1000 person years was determined in order to eliminate HIV.

Reality shows different results. At present, every untreated HIV-infected individual causes another 7 HIV infections (R0=7) in the course of their lifetime. R0 could be reduced to 4 if every person received regular treatment with therapy starting at 200 CD4 T cells/µl, or even to 3 if therapy starts at 350 CD4 T cells/µl. However, an R0 reduction to less than 1 is impossible by this method and curtailing the epidemic with ART alone remains unrealistic. This could change however, with regular testing and immediate treatment of positively-diagnosed individuals – elimination of the epidemic could be possible by 2020, even in a country as severely affected as South Africa. Compared with common practice today where ART is begun only at a certain level of CD4 T cells, immediate treatment could reduce AIDS mortality to half today’s number by 2050. Calculations showed that this initially more expensive strategy could start to be cost-saving by around 2032.

The comments to the WHO publication ranged from “provocative” (Cohen 2008) to “extremely radical” (Garnett 2008). Critics raised concerns over the risks and the absence of ethics (would all actors agree? Could a restricted individual autonomy be achieved? Can changes in sexual habits be maintained?), medical (compliance problems, the dangers of possible resistance, the side effects and “overtreatment” – starting too early) as well as financial (South Africa would have to triple their financial commitments) considerations.

Such calculations are not new. Other groups have arrived at similar results in the past (Velasco-Hernandez 20002, Montaner 2006). What is new is that antiretroviral therapies today are potentially more user-friendly and such programs are probably easier to put into practice than just a few years ago.

In addition, people are realizing that the current preventive measures can only improve slowly and that neither vaccines nor microbicides can be expected in the near future. At present, approximately 80% of the population in sub-Saharan Africa is not aware of their infection. More than 90% do not know if their sexual partners are infected – an invitation for further spread of the epidemic.

Juggling figures like this may seem unhelpful at first. Despite all objections regarding methodological, ethical, financial or logistic considerations, etc., facing 2.2 million new infections per year, a number that is not likely to decline much (if at all) in the near future, and the failure of several vaccine and prevention studies, one thing has become clear. Antiretroviral therapy has turned into one of the most important components of prevention.

Such initiatives like that of the WHO must be continued, and new and unusual strategies must be continually developed. It cannot do harm to bring more therapy to the 6.7 million people, worldwide, the number who by the end of 2007 desperately needed ART and were not receiving it (see chapter on Global Access).

ART & viral load in other body fluids

Do viral load in plasma and viral load in other body fluids correlate?  Here are some data:

  • In a study from Italy the viral load on PI-containing ART regimens decreased by several logs in plasma as well as in semen (Liuzzi 1999).
  • In a Swiss study with 114 male patients with plasma viremia under 400 copies/ml on ART, only 2 (2%) isolated viral loads were detected in semen, compared to 67% in untreated control groups.
  • In 205 HIV-infected women with plasma viremia under 400, 400-9999 and over 10,000 copies/ml, the rate of detectable HIV-1 RNA in the genital tract was 3, 17 and 48%, respectively (Cu-Uvin 2000). In 7 ART-naïve women, the viral load decreased by 0.7–2.1 logs within the first 14 days of ART. Similar results were achieved with 11 Brazilian female patients (Vettore 2006).
  • In a group of 290 women with plasma viremia under 500 copies/ml, 44 (15%) had detectable HIV-1 RNA in cervical smears (Neely 2007). In comparison to PI-containing ART the risk with NNRTIs was double.
  • In a study with 34 females with plasma viremia below 80 copies/ml, all treated with ART for at least 6 months, only one woman showed a viral load over 80 copies/ml in cervical vaginal fluid (CVF) compared to 7 rebounds in plasma (Kwara 2008).
  • Out of 122 samples of cervical vaginal lavage the viral load in the lavage correlated highly with plasma viral load (Fiore 2003). However, in 25% of cases, virus was found in the lavage even when plasma viremia findings proved negative.
  • In a study with 233 MSM (1996–1997), far less virus was found in anorectal smears of those treated with ART. Among those patients with less than 50 copies/ml in plasma, 1/54 (2%) HIV-1 RNA was detected in the anorectal smear. However, in 14/50 (28%) HIV-1 DNA was detected.
  • Among 255 MSM receiving ART with a plasma viral load below 40 copies/ml, 7 patients (3%) showed an isolated viral load in semen (Marcelin 2009). These 7 patients had been on ART for some time and treated with agents detected in semen.
  • In a prospective study on 25 Canadian patients on ART, a viral load in semen was found in 19/116 (14%) samples (Sheth 2009). There was no reference to drug concentration  in seminal fluid.

In conclusion, in most cases, viral load in plasma parallels viral load in other bodily fluids. If the viral load in plasma decreases, so does the RNA in semen or the vaginal fluid within a short time. “Below the limit of detection in plasma” also means “below the limit of detection in other bodily fluids”. In most cases. There are exceptions: in the studies above the variation was between 1 and 14%. Although there are implications that the detected virus in semen is not completely infectious (Nunnari 2002), one cannot rule out the patient being potentially infectious even on successful ART.

Putting together these facts with clinical data, transmission with a low viral load seems unlikely. To date, only a few cases have been recorded in which transmission has taken place despite effective ART (Stürmer 2008). These cases show that there is in fact a residual risk. The question is how to manage that risk.

The EKAF paper

In January 2008 a paper was released by the “Eidgenössische Kommission für Aids-Fragen” (EKAF), the Swiss AIDS commission. Just the title of this paper caused a great stir: “HIV-infected individuals without other STDs on effective antiretroviral therapy are not sexually infectious.” The original manuscript can be found at http://www.saez.ch/pdf_d/2008/2008-05/2008-05-089.PDF.

EKAF concluded that HIV-infected individuals do not transmit the disease under three conditions:

1. ART is adhered to and monitored by a clinician

2. The viral load has been below detection for at least six months

3. There is no other STD

This first official statement from public authorities on this subject had a major impact. Despite its caveats, critics feared that this publication could be misunderstood as an all-clear signal resulting in people being less careful and unnecessarily exposing themselves to risks of HIV infection.

Critics say that the data is not sufficient, especially for the risk of anal sexual contacts. The probability of infection is certainly under 1:100,000, but nevertheless not zero (Wilson 2009). The preventive effect of ART may be endangered by higher risk taking. According to mathematical models, a 10% rise in risk behavior could counter the effects of ART (Blower 2001, Law 2001). However, a meta-analysis came to the conclusion that ART does not increase risk behavior of the patient, even if the viral load is below detection (Crepaz 2004).

HIV clinicians must be prepared for this discussion. Patients are asking more questions: do I have to use a condom for the rest of my life? Here, it is better to give individualized advice. It depends greatly on the non-infected partner as well, as he or she should not be pressured. On the other hand, information of this type can be a relief for many patients and their partners. The EKAF paper may also motivate high-risk patients to finally start antiretroviral treatment (preventing more infections rather than causing new ones initially feared by the release of the paper).

However, it must be repeated that the EKAF statement refers only to stable relationships. Safer sex is still recommended, especially with occasional sexual contacts to avoid other sexually transmittable diseases.

Medical prevention strategies besides ART

Circumcision

Circumcision of the male foreskin reduces the risk of infection for several diseases in unprotected sexual intercourse (Weiss 2006). At least three randomized trials with heterosexual males in Uganda, Kenya and South Africa demonstrated this in recent years for HIV as well. Remarkably similar results were achieved (Table 12.1).

Table 12.1. Large randomized studies on circumcision.
Place

Reference

n

Main Results

Reduction of Transmission risk

Kenya
(Bailey 2007)

2784

Two–Year HIV Incidence 2.1%  (95% CI 1.2-3.0) vs 4.2% (95% CI 3.0-5.4)

53-60%

Uganda
(Gray 2007)

4996

Over 24 months HIV incidence
0.66 vs 1.33/100 person years

51-60%

South Africa
(Auvert 2005)

3274

Over 18 months HIV incidence
0.85 vs 2.10/100 person years

60-61%

TR = Transmission Risk, partly different definition/calculation

A meta-analysis of these studies shows a relative risk of 0.44 for circumcision (Mills 2008). The NNT (number needed to treat) required to prevent an event reached a relatively low number of 72.

The effect of circumcision is explained by the presence of CD4-positive Langerhans cells and primary HIV target cells in the male foreskin. Circumcision reduces the frequency of genital HSV-2 infection (Tobian 2008), which however does not explain the protective effect (Gray 2009). An estimated 2 million HIV infections in Africa alone could be prevented in the next few years (Williams 2006). The WHO recommends circumcision as a preventive means for heterosexual men. A favourable side effect is that fewer HPV-infections are transferred (Serwadda 2010)

Circumcision, however, is not without risk. Complications (infections, postoperative bleeding) occur in 3-4% of cases (Gray 2007). Sexual behavior after circumcision, ethics and logistical problems are only a few aspects (Lie 2006). It must be noted that circumcision reduces the risk for male but not for female partners. The randomized study in Uganda showed a slight increase in infections of the female partners of circumcised males (Waver 2008). This can be mainly explained by couples probably having sexual intercourse earlier than recommended. Several weeks of no-sex are stipulated after the operation.

Is there a protective effect for MSM after circumcision? If there is, the data is less clear compared to the results for heterosexual men. A meta-analysis of 15 greatly varying studies with 53,567 MSM (52% with circumcision) showed no significant difference between circumcised and uncircumcised males (Millet 2008). Another newer study confirms these results (Sanchez 2011).

Preventive treatment of HSV and other diseases

Genital infections clearly increase the risk of acquiring HIV. This applies especially to the human herpes virus 2 (HSV-2). According to a meta-analysis, the risk of HIV increases with HSV-2-seropositivity: when HSV-2 antibodies are detected in the blood, the risk increases in male patients by 2.7 fold and in female patients by 3.1 fold (Freeman 2006). A considerable amount of new HIV infections are due to HSV coinfection, with an estimated 38–69% in female patients and 8–49% in male patients.

Is a reduction of the HIV transmission rate in HIV-negative persons possible by suppression of HSV-2? HPTN 039, a double-blind, randomized, Phase III trial investigated (Celum 2008). In total, 1871 MSM from the USA and Peru and 1380 women from Zimbabwe, Zambia and South Africa received 400 mg acyclovir or placebo twice daily. Enrolled subjects were all HIV-negative and HSV-2-positive at the beginning of the trial. Although less HSV ulcers were observed in the active group, the trial failed to show a decline in HIV incidence in the acyclovir-group, with 3.9/100 person-years compared to 3.3/100 in the placebo group. These disappointing results were confirmed by the Mwanza trial with 821 women in Tanzania, in which again no decline was observed (Watson-Jones 2008). It is still not clear why, however, resistances against acyclovir is unlikely (Watson-Jones 2010).

According to current data, preventing HIV infection with HSV therapy using acyclovir has proven unsuccessful. The prophylactic use of azithromycin, to prevent bacterial STDs also showed no protective effect against HIV (Kaul 2004).

Can the transmission rate be reduced if the HIV-infected partner is treated with acyclovir? A huge study enrolling 3408 discordant African couples showed no effect of the transmission rate, albeit the clearly reduced rate of genital HSV ulcers (Celcum 2010). However, this study did show an interesting side effect, that there is a slight but measurable effect with acyclovir and its derivatives regarding HIV viral load. Compared to placebo, a decline of 0.25 logs was observed. This effect slightly decreased the risk of HIV progression in therapy naïve patients (Lingappa 2010). The transmission rate was obviously not influenced by the reduction in viral load. Resistances were not induced by acyclovir (Baeten 2011).

Antiviral effects were also observed in several other randomized studies. The viral load in blood and cervicovaginal fluids was reduced by 0.26 to 0.53 logs by using acyclovir or valacyclovir (Delany 2009, Nagot 2007, Zuckermann 2007, Baeten 2008, Dunne 2008, Paz-Bailey 2009). These studies may possibly lead to the development of new acyclovir derivatives with improved antiviral potency, provided they respond well to HIV (Vanpouille 2010).

Microbicides, lubricants, diaphragms

Microbicides are chemical agents, mostly of topical application, in the form of gels that kill or immobilize HIV and other diseases. Presently heterogenic mechanisms are being examined. Among them are inactivated agents that inhibit docking to the target cell or antiviral agents. It is required that microbicides are not only inexpensive, easy to apply and non-toxic, but also effective against other STDs, as these increase the risk of HIV-transmission. The CAPRIAL trial (see below) has led to a noticeable revival in this field of research.

Inactive microbicides: Up to now, there is no product that has delivered convincing protective effects in clinical studies. HIV transmission risk in fact increased with nonoxynol-9 (Van Damme 2002) or cellulose sulfate (van Damme 2008).  PRO 2000, which initially seemed promising, had no effect (McCormack 2010). Application of diaphragma and/or lubricants in addition to condomes had no protective effect, as one randomized study showed (Padian 2007).

Antiretroviral Microbicides: A breakthrough in research of microbicides was achieved in the CAPRISA trial in September 2010. CAPRISA was a doubleblind study, in which 889 HIV-negative women in South Africa used 1% tenofovir gel (Abdol Karim 2010). Compared to placebo, HIV incidence was reduced from 9.1 to 5.6/100 years. Transmission risk for women applying the gel regularly was reduced by 54%. This first success (“proof of concept”) has led to a focus on antiretroviral substances in the research of microbicides, such as tenofovir and even the more experimental NNRTIs dapivirine and MIV-150, as well as maraviroc and raltegravir (Review: Mertenskötter 2011).

PrEP (Pre-exposure Prophylaxis)

In the HIV setting, PrEP is an oral prophylactic antiretroviral treatment. Like malaria prophylaxis, it is taken before exposure. PrEP trials are currently being conducted in high-risk groups (i.e., commercial sex workers). Most trials use tenofovir, either alone or in combination with FTC. Such studies, however, have been regarded with criticism. Pressured by activists and others, a study with Cambodian sex workers was interrupted in 2004 and others in Cameroon and Nigeria in 2005 (Cohen 2004, Sing 2005). The researchers involved were accused of not providing sufficient information to the participants and of discontinuing treatment once the study was over.

A similar breakthrough, like the one with microbicides by the CAPRISA trial, was seen with PrEP in the end of 2010. In the iPrEx study, 2499 MSM from six countries received either TDF+FTC or placebo. After a median of 1.2 years, 36 versus 64 infections were observed and the risk for infection was reduced by 44%. Apart from slightly more cases of nausea and weight loss in the verum group, there were no differences. Only in 3/34 patients infected in the verum group, tenofovir or FTC were detected in plasma. One may argue that complete protection is not secured: However, with an alarmingly high number of 2.2 million new infections worldwide, PrEP remains an approach that must be pursued.

Table 12.2: Large randomized study on PrEP, March 2011
Country

n

Risk group, kind of  PrEP

Status, first results

Thailand

2.400

IDU: tenofovir

fully recruited, 2012

Africa, Partners PrEP Study

4.758

discordant couple: tenofovir, Tenofovir+FTC

fully recruited, 2012

Africa, FEM PrEP

3.900

women: tenofovir+FTC

49 % recruited, 2013

Africa,  VOICE/ MTN 003

5.000

women: tenofovir, tenofovir+FTC, vaginal tenofovir gel

65 % recruited, 2013

Physicians must be prepared for inquiries on PrEP, although some questions still remain that have not been answered by the above study.

How should PrEP be administered? Who will receive the treatment? And who will cover the expense? What about development of resistance in unidentified HIV infection? Will this decrease the use of condoms? Will PrEP be sold on the black market in the near future (and so, with limited adherence programs)? These are only a few aspects to be considered. In Switzerland as well as at the EMA, a commission dealing with these questions has already been set up, although the benefits of PrEP have not yet been scientifically proven.

In conclusion, with dramatically high numbers of continuing infections worldwide, prevention must strike new paths. Strictly Propagating safer sex alone is not enough. Among medical approaches, the use of antiretroviral therapy is the most imaginative strategy right now. The EKAF paper will continue to be discussed. Like it or not, microbicides and PrEP will have a lasting effect on HIV prevention. Patients will be asking for it.

Compliance

Compliance is the Achilles’ heel of every antiretroviral therapy and non-compliance the main, if not the major factor for developing resistance and treatment failure (Turner 2000). Partial viral suppression with insufficient drug levels is ideal conditions under which resistance grows. There is no doubt – ART must be taken regularly, correctly or not at all. Taking either more than 90% or less than 69% of the treatment are both associated with a lower risk of resistance (Sethi 2003). Compliance is defined as a patient’s consent and acceptance of therapy. In the mid-90s a new term “adherence”, from the English language, was adopted. Since then, the more politically correct term – “adherence” is frequently used. This term refers to both physician and patient working together to set up a treatment concept acceptable to both parties and emphasizes that responsibility for a failure of the therapy is not only the patient’s fault.

Adherence includes all factors that influence staying on a regimen, in terms of acceptability. Whichever term is used, three facts remain:

  1. The success of a treatment is endangered if medication is taken irregularly
  2. Clinicians tend to overestimate a patient’s compliance
  3. Compliance diminishes with the complexity of the treatment

Not only drug consumers, those dependent on alcohol or patients with side effects are considered “risky patients” when it comes to adherence. In several studies, depressed patients, patients living alone and younger patients have been identified as problem groups (Murri 2001, Frank 2002, Glass 2006). Positive factors are the physician’s experience, the patient’s confidence in the positive effects of ART, and social support. Race, sex or stage of disease does not seem to be relevant. The individual’s general view of illness and health, accepting modern medicine and fear of side effects are further considerations. However, all these factors vary greatly, and in the end, adherence is difficult to predict in individual cases (Lerner 1998). The physician must rely on experience and intuition.

The importance of taking drugs regularly has been demonstrated in numerous studies. In one study with 99 patients, in which compliance was evaluated via an electronic monitoring system, the rate of viral treatment failure was only 22% in patients with a compliance level of at least 95% (95% of doses taken). Failure rates of 61% and as much as 80% were measured with a patient’s adherence between 80-94% and < 80% (Paterson 2000). However, it must be taken into consideration that this much-cited study is outdated. Newer drugs, such as darunavir, with longer half-lives, higher resistance barriers and better overall pharmacokinetics may forgive a clearly higher non-compliance (Nelson 2010). In the previously mentioned study, clinicians misjudged their patient’s compliance in 41% of the cases. Nurses did better – judging incorrectly in only 30% of the cases (Paterson 2000). Adherence tended to be overestimated in other studies as well (Miller 2002). The importance of adherence was demonstrated in patients with directly observed therapy (DOT) or directly administered ART (DAART), applied in some penal institutions in the USA. In institutions in Florida, 100% of the patients in a DOT study achieved a viral load below 400 copies/ml after 48 weeks, compared to 81% in an unmonitored control group (Fischl 2001). According to one randomized study, response improved in drug-addicted patients receiving DAART (Altice 2007). More recent data indicate that effects of PI based regimen (given as DAART) are marginal and disappear rapidly as soon as the patient is on his own (Gross 2009).

Poor compliance not only leads to virologic failure. It also bears immunological consequences. In an analysis of two prospective studies, patients with a compliance of 100%, 80-99% and < 79% experienced a reduction in viral load by 2.77, 2.33 and 0.67 logs after a year. At the same time, the CD4 T cell count increased by 179, 159 and 53 cells/µl, respectively (Mannheimer 2002).

Moreover, poor adherence has clinical effects beyond surrogate markers. In a Spanish study, patients who did not take more than 10% of their drugs showed a four-fold increase of 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 adherence to ART (Paterson 2000). In addition, it should be considered that non-adherent patients increase the risk of transmission of primary resistant viruses. The basic mechanisms for development of resistance should be explained to patients. One must emphasize that, in contrast to other chronic illnesses, resistance mutations do not disappear once they have developed. Diabetes and hypertension make effective examples. These diseases may “tolerate” forgetting some tablets occasionally, but HIV is different. Blood glucose and blood pressure levels can easily be lowered again the next day, but with HIV this strategy may not work. Even short-term lapses can have irreversible consequences. And every new occurrence of resistance complicates therapy. Patients have to be made aware of these dangers. Such conversations should be repeated from time to time and become a standard component of routine care. Cooperation with special treatment discussion groups offered by patient-centered support organizations can be useful. The 12-step table below provides additional suggestions. In addition, a number of strategies on improving adherence have been investigated. They range from employment of additional nurses to telephoning patients regularly. This last one, telephone reminders, appears to not have an influence on compliance (Collier 2005).

If adherence remains poor

Despite all efforts, some patients will not succeed in improving their adherence. Physicians and other healthcare providers should not take this personally or feel offended should a patient not want to participate in the advances of medicine. Although it may be difficult to accept the patient’s views on life, disease and treatment, healthcare providers must keep tolerance and acceptance as key components in their interactions with patients. Some providers, especially those who treat selective patient populations in university settings, tend to forget the reality of routine medical practice. Rigidly upholding the principles of modern medicine usually does not help here and putting patients under pressure achieves even less. It is important to clearly outline and explain, advise, help, question and listen.

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 too readily. When resources are limited, available drugs should be distributed with care. Restraint should be applied until the reason for poor compliance is understood.

Twelve steps to improve compliance

  1. Every patient should receive a written (understandable by the patient) treatment plan, which should be reviewed at the end of the visit. It should include a telephone number to call in case of problems or questions, accessible evenings and weekends would be even better.
  2. Patient and clinician should agree on the treatment plan. The patient’s concerns, questions and criticisms should be discussed.
  3. The patient should have the impression that the treatment regimen is 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 named and offered.
  8. It is important to tell the patient to come back if any problems are encountered with ART – it is better to try 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 (avoid, “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. Pills counted, bottles checked?
  11. During all stages 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.

Duesbergians – a sect of HIV medicine

Patients who principally refuse antiretroviral treatment form a special case. These patients are frequently under treatment by (shockingly misdirected) doctors, who call themselves “Duesbergians” (after the US virologist and AIDS dissident Peter Duesberg, who denies any association between AIDS and illness). In such cases, it can be very difficult to leave patients to their fate. Informative consultations should be as detailed as possible and preferably documented in writing. Below, an example:

An approximately 40-year-old patient with a long history of untreated HIV, 30 CD4 T cells/µl and cerebral toxoplasmosis (TE), which improved significantly after 4 weeks of acute treatment (the last MRI still showed scattered lesions) introduced his case to the HIV outpatient 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. His Duesbergian physician had advised him against HIV therapy (“You can die from AZT, and the other drugs are not much better, etc”). He refused antibiotics on principal as well. This was why the patient would not continue the TE maintenance therapy, which had made him suffer from diarrhea (NB, probably cryptosporidiosis), skin problems (seborrhoic dermatitis, thrush), and extreme loss of weight (MAC?) since his first day in hospital. It was very important for him to have a break from all medication.

In such cases, we make sure the patients sign the information sheets. Every patient is allowed to and should decide for himself (if fully cognizant and capable) – they must know and be fully informed about what they are doing. It is important to give the patient control: if they changes their mind, they may return!

In our experience, arguing with medical Duesbergians leads to nothing at all. This sect has a very restricted view of the world and stick to their repetitive –mantra-like arguments. Discussing with them is time consuming and a waste of energy.

Fortunately, these cases have become rarer. The initial widespread scepticism towards ART has decreased significantly, due to its overwhelming success in the last few years. Concerning Peter Duesberg, it has become quiet, at least as far as his HIV activities goes. The sect is in decline.

Costs

Antiretroviral treatment is expensive. A health provider needs to be informed about costs for drugs.

In Germany, for example, the price for individual drugs range between €300 (Epivir®) and over €2,400 (Fuzeon®) per month, common threefold therapies range between €14,000 and €24,000 per year. Even within drug classes, there are astonishing differences. Crixivan® (hardly used today) is relatively cheap, while Aptivus® is more than three times the price. Even within primary therapies recommended in guidelines there are great price variations: PIs are almost double the price of NNRTIs in many countries. In Germany, annual costs for Kivexa®+Sustiva® are €6,400 cheaper than for Truvada®+Prezista®/r. If the integraseinhibitor Isentress®, the most expensive drug licensed for primary therapy is used instead of Prezista®,the difference is almost € 8.800 per year. A salvage therapy for a patient with multiresistant virus can amount to as much as €50,000 and more per year. Even though prices alone should not influence the choice of therapy, it is still important for the physician to be aware of the costs.

It is difficult to comprehend the price policy intended by pharmaceutical companies. The reason why prices for directly competing agents (3TC and FTC) are almost exactly the same, whilst prices for other agents of the same drug class differ by 200-300%, cannot be explained by development costs alone. There is no doubt. People are making money with ART and the market is full of competitors – monopolies and patents are being protected.

Despite all the criticism and price discussions, two facts can not be forgotten:

First, the high development costs for new medicines can rise to a billion dollars or more. Most agents never make it to the market. Even a licensed drug such as T-20 may never recoup its development costs. According to Roche, development and research alone chewed up 600 million dollars. To cover such production costs, thousands of patients worldwide would have to be treated with T-20 for several years – a very unrealistic scenario.

Second, there is hardly a more effective therapy than antiretroviral therapy. US estimations assume an expenditure of between $13,000 and $23,000 per additional QALY (quality-adjusted life year) (Freedberg 2001). Compared to many other therapies this is relatively cheap. ART reduces the cost of expensive treatment of opportunistic infections, inpatient and outpatient care. In one German study, between 1997 and 2001 total annual spending per patient decreased from €35,865 to €24,482 (Stoll 2002). Many patients return to work, resulting in an overall economic gain for society (Sendi 1999).

Nevertheless, ART is expensive. Therefore, it should be expected from patients to use up remaining packets of drugs, etc. if the reasons for a change in therapy are not urgent. Concerns of pill reduction or doubts about long-term toxicity should be part of an ongoing discussion with patients. All patients need to be made aware of the costs of medication –to make them aware of the value of the therapy.

Initially, ART should be prescribed for a month. This way, mountains of unused pills will not be wasted, if signs of intolerability or complicated adverse events set in. If response to ART is positive and its effects constant, prescriptions can then be done for a period of three months.

Many companies now offer three-month supply packages. This practice has not been without criticism. In any case, prescriptions of longer than a three months supply should be avoided.

In the future, we all need to be more aware of the costs for ART. The patents for AZT, ddI, 3TC, d4T and abacavir, but also saquinavir will disappear or have already gone. Efavirenz and nevirapine will soon follow. It will be interesting to watch price developments when generics come to the market, as they have in resource-limited settings

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Filed under 6.12. Prevention, compliance, costs, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

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