Background

While people living with HIV infection or AIDS may live many years before their infection leads to secondary diseases and eventually AIDS, survival with advancing HIV infection is complicated with symptoms and medical conditions. Many of these symptoms and conditions, and the advance of HIV itself, are manageable with drugs. However, access to even the most basic of drugs is seriously lacking in many parts of the world.

The World Health Organization (WHO) estimates that over one-third of the world's population has no guaranteed access to essential drugs. There are various reasons for this lack of access. Worldwide, the most important is affordability (drugs cost more money than is available to pay for them) but legal, infrastructural, distribution and cultural factors are also serious obstacles. The influence of each of these factors is different from country to country, just as frequencies of diseases also vary greatly.

Among its activities aimed at improving drug access in developing countries (including technical services such as help in drug procurement and performance of needs estimates), WHO has drawn up a Model List of Essential Drugs, which is updated every two years. The tenth list (1997) has 308 priority drugs that provide safe, effective treatment for the infectious and chronic diseases which affect the vast majority of the world's population. The drugs are selected on the basis of cost-effectiveness within each drug class (e.g. of the dozens of penicillins only eight appear on the Essential Drugs list).

With WHO's encouragement, more than 140 countries have developed their own national essential drug lists taking into account local needs, costs and available resources. (For more information see WHO's The use of essential drugs in the Selected Key Materials.)

The drug needs of people living with HIV

Drug access issues related to HIV infection are especially complex because HIV gradually destroys the body's immune system, which normally defends the body against a multitude of invaders. When this defence system is weakened, even relatively weak invaders may attack successfully, and cause diseases that would otherwise be rare.

Table 1 shows a list of the diseases (both opportunistic infections and malignancies) that are most often reported among people living with HIV/AIDS.

Table 1. Global frequency rates of HIV-related opportunistic infections and malignancies

Infection or malignancy	Average frequency
Oral candidiasis	53%
Pneumocystis carinii pneumonia (PCP)	24%
Tuberculosis	22%
Oesophageal candidiasis	21%
Cytomegalovirus disease	21%
Kaposi sarcoma	15%
Toxoplasmosis	11%
Cryptococcosis	9%
Cryptosporidiosis	8%
Herpes zoster	7%
Systemic herpes simplex	7%
Mycobacterium avium complex infection	4%
Salmonella septicaemia	4%
Histoplasmosis	4%

Note: Aspergillosis, isosporiasis, nocardiosis, leishmaniasis and penicillinosis were also reported, and on average had a rate of less than 4%.

Table adapted from WHO's "Standard treatments and essential drugs for HIV related conditions: Access to HIV-related drugs" (DAP/97.9)

These diseases occur in different combinations and at different rates among people living with HIV/AIDS in different parts of the world. For instance, PCP is more frequent in industrialized countries while tuberculosis is more frequent in developing countries. Such epidemiological differences mean that the mix of drugs for treating diseases and symptoms in one location may be different from that in another location. (For more information see the Technical Update on Opportunistic diseases and AIDS.)

The affordability gap

Affordability is not the only reason that people cannot obtain the drugs they need, but it is probably the single most important one. Over 80% of the world's current 30 million people living with HIV live in sub-Saharan Africa, where the average health expenditure per capita ranges from under US$ 10 in the poorest countries to around US$ 200 in the richest. In these and other developing countries, treatments for opportunistic infections such as cryptococcosis and candidiasis and antiretroviral therapy may be beyond the financial means of public health systems and of most individuals.

Price is an important part of affordability. Drug prices depend on many factors, but one of the most important is whether the drugs are proprietary (still new and under patent) or generic (not under patent, and therefore sold at a price closer to the cost of production). Because of their high price compared to generic drugs, proprietary drugs are not usually included on the World Health Organization's List of Essential Drugs (only 10% of the list is currently proprietary), nor on national lists developed by individual countries.

As HIV/AIDS is quite recent in medical history, most of the drugs created especially to treat HIV infection and its related diseases are proprietary. This renders their treatment less affordable than that of other diseases.

Gaps in supply and distribution

When ability to purchase drugs is low, it is often not profitable for drug suppliers to offer their products at all, no matter how great a need there is. This is especially true for proprietary drugs. However, some generic drugs with important benefits for people living with HIV are also not consistently available even when they appear on the WHO's Essential Drugs list.

For example, in a 1995 survey of 13 main international providers of generic drugs by Management Sciences for Health (MSH) identified a number of serious gaps (see International Drugs Price Indicator Guide in Selected Key Materials). Out of these 13 providers, only four offered codeine tablets while none offered morphine, either for oral or intravenous administration, for basic pain relief. None offered pentamidine for treatment of PCP; none offered doxorubicin, bleomycin, or vinblastine (and only 4 offered vincristine) to treat Kaposi sarcoma; none offered calcium folinate (leucovorin) to combat the side-effects of pyrimethamine treatment for toxoplasmosis. The study also found that too few galenic forms were offered, making intravenous treatment and the treatment of children difficult. For example, no pediatric formulations of antituberculosis drugs were offered by any of the 13 suppliers surveyed by MSH.

Another gap in coverage comes from the fact that some generic drugs of great benefit to people living with HIV are not on the WHO Essential Drugs list. Examples include lope-ramide and diphen-oxylate, two drugs used to alleviate intractable chronic diarrhoea (a very frequent complication of advanced HIV infection) and methadone, used in the management of drug dependence. Fortunately, loperamide was still supplied by some generics suppliers in spite of its absence from the list.

Tables 2 to 5 provide a brief look at drugs that offer significant benefits to people living with HIV and lists indicative wholesale prices, whether the drugs are proprietary, and the main obstacles to their availability and use. The tables are not meant to be used as definitive sources of pricing information (such data are constantly being updated in catalogues) but as a means of illustrating the supply side of the access to drugs question. The tables cover:

· Anti-infective agents: Table 2 lists some of the drugs most in demand to treat or prevent opportunistic diseases. Almost half are proprietary, with prices as high as several thousand dollars per year for treatment or prophylaxis, and many are not widely available in developing countries. As well, some are both difficult to administer (i.e. requiring highly trained medical staff or expensive equipment) and to monitor.

· Anti-cancer drugs: Table 3 lists drugs used to treat two of the most frequent malignancies in people living with HIV/AIDS, Kaposi sarcoma and lymphoma. Although generics exist, availability is low.

· Palliative drugs: Table 4 lists drugs needed to relieve pain and discomfort, both physical and mental, and other symptoms in people living with HIV/AIDS. Even though most of the symptoms listed can be treated or alleviated with essential drugs, access to palliative care is hampered by limited availability of major analgesics (e.g., codeine, morphine and pethidine). As well, some cheap and effective palliative drugs are classed as illegal narcotics and thus are not listed, even if the palliative benefits at a late stage of disease outweigh the risk of addiction.

· Antiretrovirals: Table 5 lists drugs that combat HIV, a retrovirus, and thereby limit the damage that the virus does to the immune system. All are proprietary, all are very expensive, and all must be used in combination in order to be effective (see WHO's Guidance Modules on Antiretroviral Treatments in the Selected Key Materials).

Table 2. Anti-infective agents frequently needed by people living with HIV/AIDS

Indication	Drug	Wholesale price* (in $)	Status	Obstacle
Cytomegalovirus (CMV) disease	Ganciclovir IV (treatment)	959/14 days	Proprietary (P)	$, A, M, O
	IV (prophylaxis)	(12 358/year)
	Oral (prophylaxis)	(21 968/year)		$, M, O
	Cidofovir IV treatment (alternative to ganciclovir)	2236/14 days	P	$, A, M, O
	(prophylaxis)	(29 071/year)
	Foscarnet IV treatment (alternative to ganciclovir)	1159/14 days	P	$, A, M, O
Herpes zoster	Aciclovir 800 mg/day oral	170/7 days	Off patent, but no generic yet listed	$, O
Extensive herpes simplex	Aciclovir 800 mg/day; injection	1283/10 days	P	$, O
	Foscarnet (alternative to aciclovir for prophylaxis)	(18 148/year)	P	$, A, M, O
MAC	Azithromycin	923/year	P	$, O
	Clarithromycin	1860/year	P	$, O
	Rifabutin	3175/year	P	$, O
Microsporidiosis	Albendazole	0.0267/tablet		Generic (G)
PCP	Pentamidine	Not listed	G	O
	Trimethoprim-sulfamethoxazole concentrate for IV administration	611/21 day treatment	G	$, A, M, O
Systemic mycosis	Itraconazole	7441/year	P	$, O
	Fluconazole	5506/year	P	$, O
	Amphothericin B	15.90/day	G	$, A, M, O
		656/42 days
Thrush	Ketoconazole 200 mg tablet (PO)	0.40/tablet	G	$
	Miconazole gel (PO)	0.02/mg	G
	Nystatin suspension	0.05/ml	G
	Nystatin tablet (PO)	0.07/tablet
Toxoplasmosis	Clindamycin	4411/year	G	$
	Sulfadiazine tablets	1.59/day (507/year)	G	O
Tuberculosis prophylaxis	Isoniazid 300 mg/tablet	5.15/year	G
Tuberculosis treatment	Anti-TB drugs	15 - 45/treatment course	G

* Source: International Drugs Price Indicator Guide, 1996. Proprietary drugs as listed in British Hospital

Formulary. Prices converted at £ 1 = US$ 1.59

Symbols: $ = high price, I = international regulations limit distribution, A = administration to patients is difficult, M = monitoring of patients is difficult, E = generic, but not on WHO Essential Drug List, O = not offered on market.

Table 3. Anti-cancer drugs frequently needed by people living with HIV/AIDS

Indication	Drug	Wholesale price* (in $)	Status	Obstacle
Kaposi sarcoma	Adriamycine (injectable)		Generic	O, A, M*
Kaposi sarcoma	Bleomycin (injectable)	25.84/15 units	G	O, A, M*
Kaposi sarcoma	Vinblastine (injectable)		G	O, A, M
Kaposi sarcoma	Vincristine (injectable)	3.97/vial	G	O, A, M
Lymphoma	Methotrexate (PO)	0.12	G	O

Table 4. Drugs for palliative care frequently needed by people living with HIV/AIDS

Symptom	Drug	Wholesale price* (in $)	Status	Obstacle
Allergy, anxiety, itching(treatment with antihistaminics)	Promethazine injection	0.1364/2 ml	Generic
	Promethazine suspension	0.0060/ml	G
	chlorpheniramine tablet	0.0030/tablet	G
	chlorpheniramine injection	0.1443/ml	G
Anxiety, convulsions	Diazepam, oral and injection	0.003/5 mg tablet;
		0.0447/5 mg ampoule
Convulsions	Sodium valproate 200 mg/tablet	0.0265/tablet	G
Depression (treatment with anti-depressants)	Amitryptiline 25 mg tablet	0.0063/tablet	G
	Amitryptiline 10 mg tablet	0.006/tablet	G
Diarrhoea	Loperamide 2 mg tablet	0.0065/tablet	G	E
Drug addiction	Methadone	Not listed	G	I, O
Epilepsy, convulsions	Carbamazepine	0.0304/tablet
Hypersecretion	Anticholinergics e.g. atropine	0.1165/0.5 mg/ml ampoule
Itching skin rash	Calamine lotion	0.0023/ml
Nausea	Anti-nausea products e.g. meclopramide	0.0055/tablet	G
Pain, cough, diarrhoea	Codeine 30 mg tablet	0.03/tablet	G	I, O
Severe anxiety, psychosis, intractable hiccups (treatment with neuroleptics)	Chlorpromazine 100 mg	0.00216/tablet	G
	Haloperidol 1.5 - 2.0 mg tablet	0.0057/tablet
Severe pain	Pethidine 50 mg ampoule (oral and injection)	0.266/ampoule	G	I, O
Severe pain	Morphine	Not offered	G
	oral solution 10 mg/5 ml			I, O
	injection 10 mg/1 ml ampoule			I, M, O

* See footnote to Table 2

Table 5. Antiretrovirals for treatment of HIV/AIDS

Drug	Wholesale price* (proprietary) (in $)	Obstacles
Delarvudine	266	$ A, M, O
Didanosine	186	$ A, M, O
Efavirenz	about 360**	$ A, M, O
Indinavir	450	$ A, M, O
Lamivudine	230	$ A, M, O
Nelfinavir	559	$ A, M, O
Nevirapine	248	$ A, M, O
Ritonavir	668	$ A, M, O
Saquinavir	572	$ A, M, O
Stavudine	243	$ A, M, O
Zalcitabine	207	$ A, M, O
Zidovudine	287	$ A, M, O

* Estimated cost to a pharmacist in the United States for a 30 - day supply (cost to patient will be higher, depending on mark-up). Source: Red Book, 1997, quoted in American Family Physician, 57(11): 2791

** Dupont-Merck Press Release, September 1998