Recent research has found considerable variation in the effects of antiretroviral therapy on viral load in different body fluids and tissue. This variability seems to correspond to the penetration of drugs into particular 'compartments' of the body, including the blood, the brain and central nervous system, the testes and seminal tract, and the cervicovaginal tract. However, multiple factors may be involved in persistence of viral reservoirs (Solas 2003).

In general, antiretroviral drugs are distributed in the body via the bloodstream, but certain barriers prevent the penetration of drugs into particular tissues. Barriers of particular relevance to HIV infection are the blood-brain barrier, which prevents some types of drugs from passing into the brain, and any barriers which might prevent the penetration of drugs into the testes, the seminal tract and the cervicovaginal tract. For further discussion of HIV in the genital tract, see Treating HIV in the genital tract in Anti-HIV therapy: Choosing your treatment strategy.

HIV and the brain

The central nervous system, including the brain, is an important reservoir of HIV infection for several reasons:

• HIV can establish infection in microglial cells, which are very long lived.

• HIV in the central nervous system can re-infect lymph nodes through the lymphatic system.

• HIV evolves differently in various regions of the brain, suggesting that HIV in the brain is to some extent an autonomous infection.

• Antiretroviral drugs may not penetrate easily through the blood-brain barrier, leading to sub-therapeutic levels of drugs in the brain.

Measuring HIV in the brain

The only way in which the impact of HIV treatment on the brain can be measured is by testing HIV viral load in the cerebrospinal fluid (CSF) surrounding the brain and spinal cord. This is not easy to do because it requires the administration of a lumbar puncture, the insertion of a needle into the spinal column under local anaesthetic. This procedure can cause subsequent pain, and is understandably unpopular. Thus, CSF levels of drugs and HIV RNA have not been tested extensively, and are not tested routinely.

HIV levels in the CSF have been linked to the development of HIV-associated brain disorders and psychiatric disease, showing that measuring CSF viral load is an appropriate surrogate for measuring HIV levels in the brain. It is assumed that measuring drug concentrations in the CSF will also provide information about drug concentrations in the brain.

A study of 138 individuals with an average CD4 cell count of 378 cells/mm³ found that those with higher baseline CSF viral loads were at a significantly higher risk of developing impairment. By contrast, HIV viral load in the blood was not seen to be predictive of developing neuropsychiatric disorders.

At baseline, tests suggested that 94 of the trial participants had no neuropsychiatric impairment, while 45 were evaluated as impaired. On follow-up, 18 of the non-impaired group were found to have developed impairment, whilst 14 of the impaired group improved to normal.

Investigators noted that not everybody with high CSF viral loads developed brain impairment, prompting them to suggest that immune responses in the central nervous system may be protective against HIV in the CSF.

Studies which have been carried out suggest that there is little correlation between HIV RNA levels in plasma and in the CSF. However, the correlation becomes stronger in HIV dementia and late stage HIV disease. It is unclear how accurately changes in CSF viral load might reflect changes in HIV infection of brain tissue.

HIV in the CSF may have a number of sources, including spill-over from productive brain infection, from HIV crossing the blood-brain barrier, or from infected CD4 cells that are moving around the body. The issue of where HIV in the CSF comes from is important because many of the currently available antiretroviral drugs do not cross the blood-brain barrier. Consequently if new HIV is being produced in the brain and the CSF, then treatments which cross the blood-brain barrier will be necessary to prevent ongoing HIV replication and subsequent treatment failure.

University of California researchers have found that HIV in the CSF has a longer half-life, decays more slowly and has greater variability than HIV in the blood plasma. This, they argue, confirms the theory of compartmentalisation, and suggests that there are two phases of HIV CSF infection: a short-term infection during early HIV infection, and a more autonomous, long-term infection in chronic HIV infection (Staprans 1999).

Dutch researchers have reported that a slower response to therapy in the central nervous system (as measured by viral load reduction) is not a consequence of poor drug penetration or the development of drug resistance, but of the presence of HIV encephalopathy (Eggers 2003). Patients with neurological symptoms but no HIV encephalopathy had significantly faster viral load reductions in the CSF.

A slower decay rate for CSF viral load has been observed to be independent of HIV encephalopathy in a study of 25 individuals receiving AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir), indinavir (Crixivan) and nevirapine (Viramune). Lumbar punctures after two months of highly active antiretroviral therapy (HAART) revealed that 36% still had CSF viral load above 50 copies/ml (Polis 2003).

Selecting a regimen that is active in the brain

The blood-brain barrier prevents many antiretroviral drugs from passing into the brain. However, the drugs which do demonstrate consistent penetration into the CSF are AZT, d4T (stavudine, Zerit), 3TC, nevirapine, efavirenz (Sustiva) and indinavir, although there seems to be considerable interpatient variability (Wynn 2002). There are few comparative data on the concentrations reached by different drugs in the CSF.

A study of 63 consecutive highly active antiretroviral therapy (HAART) patients who underwent lumbar puncture at a Rome hospital found that nevirapine, indinavir, d4T and 3TC were present at the highest concentrations in the CSF, with undetectable CSF concentrations of ddI, efavirenz and nelfinavir (Viracept; Antinori 2002). The ratio of drug in the CSF compared to the plasma ranged from 0.02 for AZT (normally thought to have the best penetration) to 0.6 for nevirapine.

Amongst the protease inhibitors, two studies have found that indinavir reaches effective concentrations in the CSF (Letendre 2000; Martin 1999). The Rome study reported that ritonavir-boosted indinavir reached concentrations an average of five times higher than indinavir dosed alone, although the margin of error was such that the lowest quartile of patients receiving ritonavir-boosted indinavir did not have significantly higher CSF levels than those with the highest blood levels taking indinavir alone. There was less overlap when boosted and unboosted levels of indinavir were compared in plasma, illustrating the degree of variability in CSF penetration. Another study demonstrated that adding low dose ritonavir to indinavir can triple indinavir levels in the CSF (van Praag 2000).

Although levels of other single protease inhibitors do not generally reach high enough levels in the CSF to have activity against HIV in the brain, dual therapy with ritonavir and saquinavir may reduce CSF viral load (Stahle 1999). Similarly, ritonavir-boosted lopinavir (Kaletra) produced concentrations of lopinavir above the level needed to inhibit HIV replication in the CSF of 26 patients with high blood lopinavir levels, interpreted by the investigators as reflecting good adherence (Capparelli 2005). However, other research has found that two protease inhibitors are unable to reduce viral load in the CSF when used without NRTIs (Gisolf 2000). For example, Dutch researchers running the Prometheus study found that CSF viral load began to decline only when 3TC and d4T were added to ritonavir and saquinavir.

Despite evidence of low PI levels in the CSF, most individuals on standard triple regimens who achieve viral load below 50 copies/ml in their blood plasma also have undetectable viral load in their CSF (Keerasungtonpong 2000). A comparative study found that AZT, 3TC and nelfinavir, and AZT, 3TC and nevirapine were equally effective at reducing viral load in the CSF to undetectable levels (Ferrer 2000).

The penetration of nevirapine and efavirenz into the CSF has been confirmed. It is unclear how many drugs within a regimen will need to be active in the brain in order to control replication and prevent the development of resistance.

The nucleotide reverse transcriptase inhibitor tenofovir (Viread) may be a particularly effective drug in HIV-infected cells other than the CD4 T-cell. Two studies have reported that tenofovir has significant antiviral activity inside dendritic and Langerhans cells, and in macrophages (Aquaro 2002; Balzarini 2002). Given that damage to macrophages plays a role in the development of HIV-related dementia, treatment with tenofovir may be a good strategic option to help protect against HIV-associated neurological disease. Tenofovir's activity in dendritic and Langerhans cells may make it an appealing post-exposure option, given that these cells are targeted during the early stages of HIV infection.

A study in 31 individuals with HIV-related cognitive impairment found that improvement in neuropsychological scores over 15 weeks after commencing a new antiretroviral therapy regimen was significantly associated with the reduction in CSF viral load. This in turn was significantly associated with the number of CSF-penetrating drugs in the new regimen (Letendre 2004).

However, two other 2004 studies in HIV-positive individuals with neurocognitive disorders have found that effective virological suppression appeared to be more important than whether or not the regimen contained a central nervous system-penetrating antiretroviral drug (Antinori 2004; Robertson 2004).

Other compartments

Although HIV is found in ocular fluid, the eye does not seem to constitute a separate pharmacological compartment as far as antiretroviral drugs are concerned. The blood supply to the eye is limited and not all drugs penetrate well into the eye. A study of 14 individuals with ocular manifestations of AIDS-defining illnesses found that within four to eight months of starting HAART, ten of 14 patients had undetectable viral load in the aqueous humour as well as in the blood (Hsu 2004).

The prostate gland is a further potential reservoir for HIV, due either to poor penetration of antiretrovirals or to bacterial infections which activate latent HIV into replication. An American study of nine men without sexually transmitted infections who all had undetectable viral load on treatment found that prostate massage could induce detectable levels of HIV in their semen, suggesting that active HIV replication continues in the prostate gland (Smith 2004).

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