Initial Treatment of Human immunodeficiency Virus-1 (HIV-1) Infection

This is an overview of initial treatment of HIV-1-infected adults with combination antiretroviral therapy (ART). We have focused on some of the major considerations which govern decision making as to when to commence ART and what to start with. The latter should always take into account other co-morbidities which may negatively affect the likelihood of success through non-adherence, exacerbation of antiretroviral-related toxicities, predisposition to well described toxicities e.g. nevirapine hepatotoxicity and higher CD4+ T-cell count and clinical status e.g. pregnancy. Although this chapter will discuss important considerations in the use of antiretroviral therapy in HIV-infected women of child bearing potential, an in-depth review of the management of HIV in pregnancy and in children is beyond the scope of this review.

Guideline: Hammer SM, et al. Antiretroviral Treatment of Adult HIV Infection. 2008 Recommendations of the International AIDS Society-USA Panel. JAMA 2008;300(5):555-570.

The hallmark of HIV-immunodeficiency is the inexorable depletion and dysfunction of CD4+ T-cells leading ultimately to the development of AIDS-defining illnesses and death. The mechanisms that underlie this CD4+ T-cell depletion are poorly understood but include direct loss via virus-induced lysis or synctia formation and indirect loss through enhanced immune destruction i.e. “bystander T-cell loss” (reviewed in (160). The viral reservoir is established early and constantly replenished even when plasma viral load is maximally suppressed (26, 27, 50). Whilst the host does mount an anti-HIV immune response that partially controls the virus - at least early in the course of the disease – this is insufficient to eradicate the virus.

In 1997, Hammer et al (68) demonstrated the first unequivocal evidence of the superiority, with respect to CD4+ T-cell increase, plasma HIV RNA decline and clinical benefit of using ART consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and a protease inhibitor vs. dual NRTI. Since this time there have been numerous randomised clinical trials and many large long-term observational studies demonstrating the survival advantages that ART affords individuals with HIV infection (45, 59, 100, 102, 120, 129, 159). Details of these clinical studies are discussed later in this review. These benefits have been seen in ART-treated patients with both advanced immunodeficiency and asymptomatic disease (159). Although the long term benefits of ART are less well described in the developing world, as large prospective cohorts have only been set up relatively recently (34), all the indications point to rates of AIDS defining illness decline with ART use which are equivalent to those in the developed world (44,145).

Immune restoration with ART can result in resolution of intercurrent infections e.g. cryptosporidiosis, and improvement in outcomes for other AIDS defining illness for which no specific therapies exist i.e. progressive multi-focal leukoencephalopathy and AIDS dementia complex (15). Moreover, the increase in absolute CD4+ T-cells allow the subsequent withdrawal of primary and secondary prophylaxes against opportunistic infections (OI) with very little risk of disease recrudescence (72). However, in patients starting ART very late in the course of their HIV infection, several immune abnormalities persist (>3 years) despite partial normalisation of peripheral CD4+ T-cell count (reviewed in 86, 87). These abnormalities include a persistent narrowing of the T-cell receptor (TCR) repertoire, dysregulation of CD4+ T-cell cytokine production and dysfunction of antigen-presenting cells including abnormal intracellular killing of pathogens by effector macrophages. The quality of the immune restoration is always poorer and the degree of immune dysregulation greater in patients starting ART at CD4+ T-cell counts less than 200 cells/µL compared to those starting at higher levels. This factor may go part way to explaining why patients starting ART at low CD4+ T-cells counts always have a higher risk of HIV disease progression than those starting with counts ≥200 cells/µL, even though the risk is substantially reduced in both groups. In patients with CD4+ T-cells <100 cells/µL starting ART with or without an active OI there is also a risk of immune restoration disease (reviewed in (126)) and in those being concurrently treated for an active OI, the added problem of drug-drug interactions. The latter is particularly problematical when patients are being treated for mycobacterial disease with rifamycins (15). Collectively, these arguments support a view that treatment should be initiated relatively early in HIV disease before profound immunodeficiency and the onset of symptomatic disease.

The main limitations of ART include failure to eradicate virus (51,173), the probable lack of any long-term impact on viral set-point if ART is ceased (177), and the short, medium and long-term toxicities of ART (23, 52, 53). Ultimately viral escape can occur due to the development of resistance (reviewed in (28)). Risk factors for treatment failure include transmitted resistance i.e. at primary infection (143) or subsequently i.e. “super-infection” (61, 74, 151,178), poor drug adherence (13, 29, 90, 124), drug–drug interactions leading to sub-therapeutic levels of antiretrovirals, co-morbidities such as co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) (18,101,144) and variable potency of different ART regimens. These issues are discussed further in section 6 of this review.

As described in the current Department of Health and Human Services guidelines (72) and the British HIV Association antiretroviral guidelines (73) the goals of therapy in the antiretroviral-naïve patient are to:

Once the decision to initiate ART has been made, the patient must be monitored closely from the perspective of their virological and immunological response, adherence and tolerability. Side-effects which necessitate a switch are those which are life-threatening or interfere significantly with the patient’s QoL. Expected declines in plasma HIV RNA level should be at least a 1 log10 copies/mL after 4 weeks of therapy and patients should have viral load below the level of quantification (generally <400 copies/mL) after 4-6 months of therapy and <50 copies/mL by 48 weeks (72). However, there is a caveat in so much as intermittent plasma HIV RNA “blips” are common and appear to represent biological, sample assay and statistical variations around the mean plasma HIV RNA of <50 copies/mL rather than clinically significant elevations of plasma HIV RNA (114). Factors to consider if these milestones are not being met are primary resistance or on-treatment resistance perhaps related to poor adherence and drug-drug interactions leading to sub-therapeutic drug levels.

Guideline: Aberg JA, et al. Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009;49:651-681.

Data from multiple cohort studies have irrefutably demonstrated that it is the first ART regimen which has the greatest chance of achieving durable virological suppression (40, 122, 130, 131) provided it is selected with due care and the factors outlined above are considered. Three-drug combinations with either two NRTI and either a protease inhibitor or non nucleoside reverse transcriptase inhibitor (NNRTI) have become the “standard-of-care” approach for HIV infection (58, 63-65, 68, 70, 71) and it is clear that starting all three drugs simultaneously is associated with a better outcome than a staggered approach (64). The question of whether there is any advantage to using a 4 drug combination from 3 drug classes as first line therapy was addressed in both the INITIO study (31) and ACTG 384 (146) with no benefit demonstrated with the addition of a third class with respect to duration of successful HIV-1 treatment. Boosting protease inhibitors by utilising small doses of ritonavir (/r) i.e. 100 – 200 mg twice a day to increase the levels of the other protease inhibitor in the combination is recommended as the “preferred” PI option in ART-naïve patients. Some unboosted PI are recommended as alternative PI (see Table 2.1). Both the Department of Health and Human Services and British HIV Association guidelines recommend the use of ritonavir-boosting in ART-experienced patients as ritonavir-boosting is an important component in increasing the area-under the curve for the primary protease inhibitor and either preventing or overcoming viral resistance (reviewed in (54)). The Department of Health and Human Services and British HIV Association guidelines make recommendations on the basis of data from properly conducted, well designed randomised clinical trials in ART-naïve patients with the caveats that:

- These results probably represent the best possible outcomes in a cohort of well selected and presumably adherent patients;

- The outcomes of the majority of these studies are based upon surrogate markers of efficacy i.e. CD4+ T-cell changes and plasma HIV RNA and not on clinical endpoint data.

The licensed drugs are shown in Table 1. Regimens have been designated as “preferred” or “alternative” on the basis of existing efficacy and safety data (Tables 2.0 and 2.1). All recommended regimens have a “backbone” of two NRTI. There is further discussion regarding the choice of NRTI backbone below. The preferred regimen is “class sparing”, i.e. preserves at least one class of widely available antiretroviral agent for future use. At present there are insufficient data to make any recommendation on the use of the following ART regimens or strategies:

- NRTI-sparing regimens including those using new classes of antiretroviral agent i.e. integrase inhibitors, fusion inhibitors or chemokine receptor-5 (CCR5) blockers;

- the use of single class regimens i.e. using PI monotherapy or dual or triple PI combinations;

In addition, neither the DHHS or BHIVA guidelines recommend the use of triple NRTI combinations (Trizivir®) due to suboptimal virological performance (72); the use of quadruple NRTI combinations should not be used outside of clinical trials. It is beyond the scope of this review to discuss the pharmacokinetic and side-effect profile of all available approved drugs (Table 1), but the reader should refer to the guideline documents carefully (72,73).

Since January 2008 the NRTI backbones recommended in the Department of Health and Human Services guidelines are coformulated abacavir/lamivudine (Kivexa®/Epzicom®) or tenofovir/emtricitabine (Truvada®); both can be given once daily with potential advantages for adherence. Coformulated zidovudine and lamivudine (Combivir®) given bid, is now listed as an alternative NRTI backbone as is didanosine plus lamivudine. In the BHIVA guidelines, Truvada® is the only preferred NRTI backbone. The DHHS and BHIVA makes these recommendations on the basis of superior virological suppression and better tolerability of tenofovir and emtricitabine compared to Combivir® with efavirenz at 48 weeks (55), the 3 year data from the Gilead 903 licensing study for tenofovir (56) and studies demonstrating the bioequivalence of the fixed dose combination (Truvada®) and the individual components (6). Truvada® is well tolerated for the most part. However, there are still some anxieties in regard to renal toxicity which can manifest in its most sever form as a drug-induced Fanconi syndrome. The exact extent of renal toxicity with use of tenofovir, and the risk factors for renal impairment have not been formerly identified, although older age, longer duration of HIV and other risk factors for renal disease are implicated. Regular monitoring of creatinine clearance (“eGFR”) and dipstick urine to identify proteiniuria are recommended. The DHHS also, recommend the use of coformulated abacavir/lamuvudine (108) as a preferred NRTI backbone only in those who test negative for HLAB*5701. This genetic test has been shown to predict patients who are likely to develop an abacavir-related hypersensitivity reaction (HSR), which has previously been observed in 5-8% of patients commencing the drug (96, 94, 139). The high sensitivity and negative predictive value of this readily available (at least in the developed world) test means that clinicians are better able to screen out patients who will develop abacavir intolerance with the caveat that a negative HLAB*5701 test does not completely negate the risk of an HSR. In terms of efficacy, abacavir was virologically equivalent to zidovudine at week 48 in the CNA30024 study (38); CD4+ T-cells were significantly higher over the same time period (+209 vs. +155 cells/µL respectively) in those receiving abacavir. In a head-to-head study of Kivexa® vs. Truvada® when given with lopinavir/r, Kivexa® was non-inferior (both virologically and in regard to toxicity) (152).

The reasons why the BHIVA guidelines still recommend Kivexa® as an alternative backbone is two fold. First, data from the ACTG5202 study (135), released after the latest version of the DHHS guidelines, showing that Kivexa® was associated with a significantly higher rate of virological failure (HR 2.3; 95% CI 1.46-3.72) compared to Truvada® (given with either efavirenz or ritonavir-boosted atazanavir) in those with baseline plasma viral load of >100,000 copies/mL. As a consequence, Kivexa® use was ceased in the higher viral load stratum. Second, data from the D:A:D study (35), showed an increase in myocardial infarction in people receiving abacavir compared to those receiving zidovudine, stavudine or lamivudine. Similar but less marked cardiovascular risk was seen with didanosine. There was no data provided on cardiovascular risk with tenofovir.

Combivir® is now an alternate NRTI backbone in the DHHS and BHIVA guidelines largely because of poor early tolerability (headache, gastrointestinal upset and anaemia) and a body of data implicating zidovudine in peripheral fat loss. However, in antiretroviral naïve women considering pregnancy, Combivir® remains the preferred NRTI largely due to its long safety track record in this setting (72). While both tenofovir and abacavir have been considered lipid and lipodystrophy friendly backbones in comparison to the thymidine analogues, zidovudine and stavudine (reviewed in (115)) the data from D:A:D is a cause for concern in regard to the use of abacavir.

In summary, clinicians should exhibit caution pending further data on abacavir in those with high Framingham scores especially as the mechanism of increased cardiovascular risk is not fully understood but does not appear to relate to lipid changes per se.

Overall, the side-effects of lamivudine and emtricitabine appear similar – at least to date - with respect to haematological, neurological and gastrointestinal side effects; however, hyperpigmentation particularly affecting the palms and soles is reported in two percent of individuals using emtricitabine with higher rates in people of Afro-American origin. Overall, lamivudine and emtricitabine appear to be very similar in potency, patterns of resistance and safety and for this reason these drugs are considered equivalent in the guidelines (138).

The factors that will govern the recommended NRTI combinations in future will include efficacy (in patients with high baseline viral load) and cardiovascular safety of abacavir-based regimens; any emerging long-term side-effects of tenofovir on renal function and bone mass (2, 78, 117); and emergence of resistance related to the first line NRTI backbone and how this impacts on future options (172). The combination of stavudine and didanosine should be avoided because of unacceptable hepatoxicity and lactic acidosis particularly in pregnant women, lipodystrophy syndrome and other manifestations of mitochondrial toxicity including pancreatitis and peripheral neuropathy (77). The combination of didanosine and tenofovir (and this is not recommended in the guidelines) should be avoided, reasons for this include the risk of toxicity associated with increased levels of didanosine, the negative impact on CD4+ T-cell levels (12, 81, 82) and early virological failure which resulted in the early closure of two clinical trials when this NRTI backbone was combined with efavirenz (92, 133).

The Department of Health and Human Services and British HIV Association guidelines recommend an NNRTI- or protease inhibitor-based regimen as the best choice in ART-naïve patients. The BHIVA 2008 guidelines now recommend an efavirenz-based regimen for a number of reasons outlined below, whereas the DHHS guidelines do not make a particular recommendation in favour of either class (Table 2.0 and 2.1). Original concerns about the potency of NNRTI (in particular efavirenz) as first line treatment particularly in patients with high plasma HIV RNA (165) have not been borne out by subsequent clinical trials, where if anything they have usually out-performed – in terms of efficacy - the comparator protease inhibitor (136) especially if this was not boosted with ritonavir (154,155). Efavirenz is the preferred NNRTI; nevirapine is recommended as an alternate NNRTI even thought the drug appears virologically equipotent to efavirenz (except in those with very low baseline CD4+ T-cell counts) (165) and the unboosted PIs, nefinavir and indinavir (IDV, Crixivan^®) (both now virtually obsolete in the developed world) (132,163). The rationale for this is the more favourable toxicity profile of efavirenz with respect to rash and hepatitis (especially in those co-infected with hepatitis viruses) (24, 97). Moreover, there is an increased likelihood of these toxicities if CD4+ T-cell counts are higher than 400 cells/µL for males and >250 cells/µL for females (14, 89, 164, 165). For this reason nevirapine should not be used in patients with CD4+ T-cells counts above these thresholds. Efavirenz has the disadvantage of CNS toxicities leading to insomnia, poor concentration, vivid dreams and vertigo in some individuals. In addition, efavirenz is an FDA category D drug in pregnancy and must be avoided in women of childbearing potential who are planning pregnancy (162).

The major drawback of the NNRTI class is the low genetic barrier to resistance and cross resistance, such that non-adherence will be associated with the development of resistance and the potential loss of at least the first generation NNRTI for future use (79, 85, 123). However, in adherent patients, NNRTI-based combinations have proven long-term durability (6, 56). In favor of efavirenz, is once daily dosing and very low pill burden (one pill qd for efavirenz coformulated with tenofovir/emtrictabine as Atripla®). While efavirenz has always been considered “lipid friendly” profile compared to most boosted protease inhibitor including Kaletra®, however, elevations in total and LDL cholesterol are seen with efavirenz and somewhat surprisingly in the ACTG5142 study (136) there was 20% more peripheral fat loss detected by DEXA in those receiving efavirenz compared to those receiving ritonavir-boosted lopinavir. On the other hand, ritonavir boosted protease inhibitors generally have a higher genetic barrier to resistance with less likelihood of developing resistance in those with poorer antiretroviral adherence (10,11). The downside is their well known association with gastrointestinal side effects and metabolic disturbance (23, 24), generally higher pill burden and until recently, their requirement for at least bid dosing. Ritonavir-boosted atazanavir (discussed below), has many of the attributes that favour the use of NNRTI (a more lipid friendly profile, low pill burden and dosed once daily) without the low genetic barrier to resistance (7). It is now one of the preferred boosted protease inhibitors in both guidelines.

The nine protease inhibitors that are currently approved by the Food and Drug Administration for the treatment of HIV infection are shown in Table 1. There is no doubt that the genetic barrier to resistance to protease inhibitors has been raised through the use of boosting doses of ritonavir (30), a potent inhibitor of the P450 CYP3A4. This effect is explained in part by the relationship between plasma drug concentrations and virological response to several agents. The ratio of drug concentration at trough (Cmin) to a measure of susceptibility to a drug is referred to as the inhibitory quotient. Several studies have now shown a correlation between the normalized inhibitory quotient of ritonavir-boosted protease inhibitors and virological outcomes (171). In addition, ritonavir boosting has allowed qd and bid dosing and reduced pill burden for patients – advantageous in terms of adherence and QoL. However, the down-side of ritonavir boosting is the potential for drug-drug interactions with other drugs metabolized through the CYP3A4 pathway, especially those drugs with a narrow therapeutic index. In addition, even the relatively small doses of ritonavir used for PI-boosting appear to contribute to drug-induced syndrome X associated with the long term use of protease inhibitors (24,30, and reviewed in (60 and 33)). There is a data suggesting that these metabolic abnormalities do contribute to an increased risk of cardiovascular events in people on PI-based compared to NNRTI-based regimens (53; reviewed in (33)).

One of the previously most commonly used protease inhibitors, nelfinavir, is no longer recommended as either a preferred or alternative the protease inhibitor in the DHHS and BHIVA guidelines, largely because of the superior efficacy of both lopinavir/ritonavir (166) and efavirenz in clinical trials, as well as its high pill burden and gastrointestinal side-effects. There are now three preferred protease inhibitors, all ritonavir-boosted i.e. coformulated lopinavir/rritonavir (Kaletra®) given bid, ritonavir-boosted atazanavir qd and ritonavir-boosted fosamprenavir given bid. Unboosted atazanavir, fosamprenavir, rionavir-boosted saquinavir and once daily co-formulated lopinavir/rritonavir are alternate PI in the DHHS guidelines. The BHIVA guidelines are less proscriptive in their recommendations for PI in antiretroviral naïve patients, largely as they recommend an efavirenz-based regimen for initial treatment. In the BHIVA guidelines, PIs reviewed for initial treatment include coformulated lopinavir/ritonavir, and ritonavir-boosted saquinavir/atazanavir/fosamprenavir and darunavir. The latter is not approved by either the European Medicines Agency or FDA for use in antiretroviral naïve patients, although an application for approval is expected in 2008.

The data supporting the recommendation of the preferred PI is based on a number of randomized clinical trials, summarized below:

- coformulated lopinavir/ritonavir (Kaletra®). There is 7 year data showing the durability and long-term tolerability of lopinavir/ritonavir based regimens (110,83), with 59% of patients still with plasma viral load <50 copies/mL at 7 years of follow-up. Once daily lopinavir/r is an alternate PI regimen as while overall efficacy was equivalent to bid dosing (99), patients with baseline plasma viral load >100,000 copies/mL were more likely to fail qd lopinavir/ritonavir (99,116), probably because of the lower Cmin from qd dosing. Once-daily dosing must be avoided in pregnancy due to altered distribution of the drug (72);

- The licensing studies for atazanavir showed the drug was equivalent to nelfinavir (109,142) and efavirenz (154). It is only relatively recently that robust data for the virological efficacy and tolerability of once daily ritonavir-boosted atazanavir has been provided. First, when compared to ritonavir-boosted fosamprenavir (93,153) and second in a head-to-head study with lopinavir/ritonavir with a Truvada® backbone. In the CASTLE study, 76% on lopinavir/ritonavir vs. 78% on atazanavir/ritonavir had VL <50 copies/mL at 48 weeks (103). It is noteworthy that elevations in lipids (total cholesterol, non-HDL cholesterol and triglycerides) were significantly lower with atazanavir/r in comparison to lopinavir/ritonavir. Atazanavir must always be ritonavir-boosted when included in a tenofovir containing regimen. The most common side-effects in unconjugated hyperbilirubinaemia which is reversible on cessation of the drug and due to temporary inhibition of UDP-glucuronosyltransferase (7);

- While unboosted fosamprenavir can be given as an alternate PI (123), ritonavir-boosted fosamprenavir is a preferred PI in antiretroviral naïve patients; treatment experienced patients must always receive the drug boosted. Data supporting the recommendation comes from the head-to-head study of fosamprenavir/ritonavir vs. lopinavir/ritonavir with an abacavir/lamivudine backbone (49). In summary, fosamprenavir/ritonavir was equivalent to lopinavir/ritonavir in regard to antiviral efficacy, safety, tolerability.

Ritonavir-boosted saquinavir (hard gel capsules or tablets) is recommended as an alternative PI based on the results of the GEMINI study (167). In this head-to-head comparison with lopinavir/ritonavir, both given bid, with a tenofovir/emtricitabine backbone, the drugs were virologically equivalent with similar increases in CD4+ T-cell count at 48 weeks. The GEMINI study added to the body of data supporting the recommendation of saquinavir/r as an alternate PI (42,43). There are also data to support once daily dosing of ritonavir-boosted saquinavir (3), although the guidelines do not recommend this. Hard gel saquinavir appears better tolerated than soft gel saquinavir with respect to gastrointestinal side-effects. The latter has now been withdrawn, and replaced with a 500mg saquinavir tablet, which has the additional benefit of reducing pill burden.

There are now 6 classes of antiretroviral agents and these are shown in Table 1. Raltegravir is a first-in-class strand transfer inhibitor of the HIV integrase; maraviroc is a first-in-class small molecule CCR5 receptor blocker. Both drugs are licensed for use in treatment-experienced patients with viral resistance and/or evidence of virological failure to non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors and protease inhibitors (72, 84,112). While neither of these exciting new drugs are licensed for use in antiretroviral naïve patients, it seems likely that an application will be made for approval of raltegravir in treatment naïve patients in the next year, when 96-week data from the ongoing studies is available. To date, raltegravir has exhibited extraordinary virological potency (95, 32, 156) and a very favourable safety profile. The drug does not require ritonavir boosting and has the added advantage of being metabolised via glucuronidation not via the P450, which effectively negates the risk of drug-drug interactions universal to drugs metabolised via or impacting on the function of this degradation pathway. Unfortunately, at the present time, it seems unlikely that maraviroc will receive approval for use in antiretroviral naïve R5- tropic HIV-infected patients as the MERIT study (140) showed the drug was virologically inferior to efavirenz when given with a Combivir® backbone. Vicriviroc, another CCR5 blocker is in phase III clinical trials. While there is increasing interest in the utilization of NRTI-sparing regimens in antiretroviral naïve patients, it seems likely that at least for the next few years, they will continue to remain the backbone of all current regimens recommended in this group of patients.

FDA. Expanded indication for Selzentry (maraviroc). Only the following information in the pdf as an abstract. Readers can read the detailed information by the "live" link to Drugs@FDA in .pdf format.

There are a number of important factors to consider when starting ART, and some of these are compromised where there is limited access to ART. Achieving treatment goals is a balance. Considerations that will increase the likelihood of success are:

- choosing a combination that is potent, and well tolerated in the short, medium and long-term; - choosing a combination that will preserve future treatment options;

- taking into consideration other co-morbidities in particular active opportunistic infections, hepatitis B and C co-infection, depression and active illicit drug or alcohol use that increase the risk of treatment failure through non-adherence and increased risk of ART-related toxicities.

The CD4+ T-cell count - at the time of treatment initiation - is a stronger predictor of AIDS free survival than plasma HIV RNA level (45) and all current guidelines advise commencement of ART based upon levels of CD4+ T-cells as described below. In addition, the CD4+ T-cell count is also an independent predictor of all cause mortality, including deaths which are probably HIV-related but are not officially classified as AIDS defining illness e.g. Hodgkin’s lymphoma (45,102). Within the existing guidelines (72, 73, 176) there is consensus that all patients with symptomatic HIV disease (including HIV-related nephropathy) or an AIDS defining illness in the setting of chronic HIV infection should receive ART irrespective of their CD4+ T-cell count.

However, there are a number of areas where there is no consensus: - the exact timing of the introduction of ART in patients with an active opportunistic infections

– although ART is definitely indicated in this setting; - treatment of symptomatic and asymptomatic primary infection;

- the point at which ART should be initiated in patients with asymptomatic, chronic HIV infection;

The initial hope that treatment during primary infection followed by treatment interruption with or without vaccination would alter the viral set point and clinical course of HIV has not been borne out in several clinical trials (reviewed in (150)). As such, treatment of primary HIV infection is not currently recommended. However, patients should be encouraged to participate in clinical trials in order to better understand the role of ART in this setting (174); results of the SPARTAC study are expected in 2010.

All patients with CD4+ T-cells ≤ 200 cells/µL should commence ART. The rationale for this is the strong cohort data supporting treatment in this group (45,59,100,102,115,129,159) in order to improve survival and prevent the development of symptomatic HIV infection including AIDS defining illnesses.

Asymptomatic HIV infection with CD4+ T-cells ≥ 201 cells/µL to <350 cells/µL

Both the British HIV Association and Department of Health and Human Services guidelines (72,73) advise commencing treatment in asymptomatic patients with CD4+ T-cells in this range. However, there is a paucity of randomized clinical trial data regarding clinical outcomes in this patient group and indeed in patients with CD4+ >350 cells/µL. The recommendation has been strengthened by data from cohort studies including the CASCADE collaboration (which collects pooled data from 22 cohorts) (98) showing that that the 6 months rate of AIDS continues to decrease with higher counts in the 200-500 cells/µL range and is much lower for patients with CD4+ >350 cells/µL compared to those with CD4+ between 200-349 cells/µL (25). In addition, the risk of AIDS continues to decline after the commencement of ART even at higher CD4+ i.e. above 350 cells/µL (45). Data from the SMART study, a treatment interruption trial that enrolled 5,472 participants with a CD4+ count >350 cells/µL, are consistent with these cohort data. In SMART (161), continuous ART (VS arm) protected substantially against AIDS, serious non-AIDS (including non-AIDS malignancy) (148) and all cause mortality compared to the drug conservation (DC) arm (re-initiation of ART only when CD4+ dropped to 250 cells/L). Although the numbers were small, this protective effect of ART was seen at all CD4+ cell levels in a subgroup of participants who were ART–naïve at study or participants who had previously taken ART but had stopped (for >6 months) prior to randomization (47). In this subset, the hazard ratio for serious non-AIDS events was 7.1 (95% CI:1.6-31.5) compared to those starting continuous ART following randomization.

At the present time, neither the British HIV Association nor Department of Health and Human Services guidelines recommend ART in asymptomatic patients with CD4+ T-cells ≥350 cells/µL. The potential benefits of deferred therapy include preservation of treatment options and reduced risk of ART-toxicity including cardiovascular events (35) because of less drug exposure. However, the downside is the probable irreversible loss of components of the immune system – the long term effects of which are unknown - increased risk of death, AIDS defining illnesses and serious non-AIDS events (cardiovascular disease, malignancy, stroke, liver-related complications, end-stage renal disease) (37, 128, 88, 121), and from a public health perspective, increased potential for HIV transmission. Moreover, deferring ART might be associated with other deleterious effects including neurocognitive disease as a consequence of ongoing immune dysregulation in the central nervous system (19). Taken together, these cohort data and data from the SMART study coupled with access to durable and well tolerated ART suggest that earlier ART treatment might have substantial clinical benefits. To this end, a randomized clinical endpoint study (START) is due to commence in 2008/9. This study will explore the clinical benefits in regards to AIDS, serious non-AIDS and all cause mortality of immediate vs. deferred (when CD4+ <350 cells/µL or symptoms develop) ART in asymptomatic HIV-1-infected adults with CD4+ counts of >500 cells/µL.

The questions of “when the best time to start ART” will not be answered for at least 5 years. So, in the interim, clinicians should strongly encourage their asymptomatic patients with CD4+ T-cells nearing 350 cells/µL to consider starting ART. Patients who choose to defer therapy until their counts drop to lower levels should be commenced on the appropriate primary prophylaxis against opportunistic infections (as applicable) and closely monitored with clinical assessment and measurement of CD4+ T-cell count and plasma viral load every 2 to 4 months (1,72).

Co-existent medical conditions must be considered when commencing ART. These include, in particular, pre-existing ischaemic heart disease (52,53), renal disease (see below), psychiatric illness and viral hepatitis co-infection (see below). Women of childbearing potential should be offered optimal ART regimens taking into consideration that some antiretroviral drugs may decrease the effectiveness of oral contraceptives (175). In addition, ART should be selected such that if pregnancy does occur, there is the least chance of teratogenicity and harm to the mother. Hence where possible efavirenz should be avoided. If there is no suitable alternative, women must be counselled about the need to avoid pregnancy whilst taking this drug and suitable alternatives offered should they wish to become pregnant. ART is recommended for all pregnant women (72, 73), irrespective of their clinical status, CD4+ T-cell count or plasma HIV RNA in order to minimize the risk of perinatal transmission. For ARV-naïve women who become pregnant, ART should commence by week 20 at the very latest if the rationale for the commencement of ART is purely to prevent vertical transmission. ART should be commenced as soon as possible in pregnant women if the ART is being used for the protection of the woman’s health. The same rationale in the choice of ART for the pregnant woman as for a non-pregnant female should be employed, except of course teratogenicity and the pharmacokinetic profile of specific antiretroviral agents must be considered. The drugs for which there is the largest amount of safety data are zidovudine, lamivudine and lopinavir/ritonavir (72). Nelfinavir is no longer recommended due to contamination of the drug with a potential carcinogen in 2007. This resulted in withdrawal of the drug in September 2007. It has since been cleared for use in males and non-pregnant females. Drugs that must be avoided in pregnancy include efavirenz, didanosine and stavudine. Nevirapine can be used but with extreme caution in women with CD4+ T-cells counts >250 cells/L; ritonavir-boosted saquinavir is also listed as an alternate PI in pregnancy. It is important that prior treatment history is considered in women with a history of multiple pregnancies as women exposed to single dose nevirapine in the intra-partum period may well have archived NNRTI resistance (79, 85).

Increasingly, genotypic and/or phenotypic testing is being performed in treatment-naïve patients with chronic infection, especially if the patient was infected in a geographical location where levels of transmitted drug resistance are high i.e. ≥5% (143). Both the DHHS and BHIVA guidelines recommend resistance testing in antiretroviral naïve patients. Physicians should be aware that these results, especially if testing takes place years after HIV seroconversion, may not accurately reflect any archived mutations due to reversal of mutations in the absence of drug-related selection pressure. In addition, clinicians should be aware of prior receipt of single dose nevirapine to prevent vertical transmission of HIV-1 in female patients or the perinatally or infected breastfeeding children of women treated with short course antiretroviral regimens. This issue is applicable in the developing world, where single dose nevirapine has been the mainstay of prevention of mother-to-child-transmission. If primary resistance mutations exist (79,85), the antiretroviral naïve patient should be treated as if they have had prior drug exposure and the genotype (if available) utilized to guide the best choice of ART. However, even if NNRTI mutations are not detected following single dose nevirapine exposure, there are data showing a poorer response to ART containing NNRTI presumably due to the presence of archived NNRTI mutations (79). In future, antiretroviral strategies which effectively reduce mother-to-child transmission without compromising future prevention of vertical transmission in subsequent pregnancies or response to ART once maternal treatment starts need to be developed. Such approaches are the subject of ongoing studies in the developing world and include the use of nucleoside analogues such as Combivir® or a protease inhibitor based regimen to cover the decay kinetics of single-dose nevirapine (reviewed in (67)).

Co-morbidities that require ongoing drug treatment may impact on the choice of antiretroviral medication because of the potential for drug-drug interactions (175). While the place of therapeutic drug monitoring (TDM) in clinical practice has not yet been established, it may find a place in the management of patients where drug-drug interactions are predicted e.g. tuberculosis-HIV-co-infection (16).

Assessment of a patient’s willingness to adhere to ART is critical to the success of the treatment in terms of a durable virological and immunological responses and preservation of future treatment options by minimising the risk of resistance. Outcomes appear to be better in those with higher adherence as discussed below (9,62,69,76). Adherence assessments should be taken prior to commencement and repeatedly whilst on therapy. The cornerstone of success is the correct timing of ART introduction (“patient readiness”), simplification of the regimen without sacrificing potency, education (“what to expect” and “what to do”) and a supportive healthcare environment. Paradoxically, however, the risk of resistance seems to rest not only upon the level of adherence but other factors including elimination half life, potency of the drugs and genetic barriers to resistance. For example, those who are poorly adherent on a non- nucleoside reverse transcriptase inhibitor (NNRTI) have a relatively high risk of resistance (123). In contrast those who adhere better have a greater risk of resistance when using an unboosted protease inhibitor (8,9,57,168), than those who are poorly adherent. The long term correlations between levels of adherence and resistance with ritonavir-boosted protease inhibitors is unknown although the development of resistance is less likely with the use of the latter (8,10,11).

Patients with HIV infection should always be screened for hepatitis B (HBV) and C (HCV) co-infection as part of routine standard-of-care practice (1). Viral hepatitis co-infection has a considerable impact on the choice of antiretroviral therapy and may influence the timing of ART commencement especially if treatment of hepatitis C with pegylated interferon and ribavirin is available and warranted (18, 41, 113, 144, 147). There is increasingevidence that liver-related deaths are contributing substantially to the HIV-related mortality in the ear of potent ART, especially in those with viral hepatitis coinfection (169).

- avoidance of drugs which may interact with ribavirin i.e. zidovudine, didanosine and stavudine;

- where possible avoidance of monotherapy for hepatitis B in co-infected patients who are commencing ART which contains drugs with anti-HBV activity i.e. lamivudine alone. At the present time tenofovir alone or in combination with lamivudine or emtricitabine is recommended.

Immune restoration disease (IRD) has been described in the setting of many opportunistic infections (reviewed in (126)) and is a particular risk for patients with an active opportunistic infections with a CD4+ T-cell count of <100 cells/µL starting ART. Until recently there has been a paucity of objective data to guide the timing of ART in patients with recent opportunistic infections (OI). The ACTG 5164 study (179) randomized patients with an OI to immediate start of ART (within 14 days of diagnosis) vs. deferral of ART for at least 4 weeks after diagnosis and treatment. Patients with tuberculosis were excluded. The OIs at baseline were Pneumocystis jirovecii pneumonia (PJP) 63%, cryptococcal meningitis 13%, pneumonia 10%. The immediate and deferred arms started ART at a median of 12 (range 9-13 days) and 45 (range 41-55) days, respectively, after treatment for the opportunistic infection had started – so all started ART within 2 months. The immediate treatment arm had fewer deaths/AIDS progression, a longer time to death/AIDS progression and a shorter time to achieving an increase in CD4+ T-cell count to >50 and >100 cells/µL. The timing of ART in the setting of mycobacterial disease is still problematic due to little objective data; in addition drug-drug interactions between anti-mycobacterial agents with many antiretroviral agents has proved clinically challenging as have the problems of overlapping toxicities. Clinicians should refer to specific treatment guidelines for guidance on the treatment of tuberculosis in the HIV-infected person (72); these were updated in June 2008.

There is increasing awareness of the renal axis in HIV-infected individuals especially as the population of individuals currently being treated in the developed world is now ageing. Consideration should be given to the recent IDSA guidelines (66) which specifically suggest the use of regular estimates of creatinine clearance (although none have been specifically validated in the setting of HIV-infection) and urinalysis in those with a normal creatinine or creatinine clearance for the detection of proteinuria. Those at higher risk of renal disease i.e. African American patients, those with a CD4+ T-cell count of <200 cells/µL or plasma HIV RNA ≥4000 copies/mL and those with hypertension, diabetes mellitus and hepatitis C co-infection should undergo annual screening for proteinuric renal disease. In addition, the guidelines give directives on how to dose adjust antiretroviral drugs that undergo renal excretion in patients with chronic renal disease or end-stage renal disease. These drugs include didanosine, lamivudine and tenofovir. However, anxiety re the potential nephrotoxicity of tenofovir in patients who do not have overt renal disease do not appear to be have manifested – at least in the short term (78, 117, 170) - although tenofovir levels are increased by 32% and 22% in patients concomitantly treated with lopinavir/r and darunavir/r respectively. This potential interaction needs to be monitored carefully as suggested above.

Much of the evidence underpinning ART has been obtained from clinical trials and cohort studies in male subjects in developed world countries, and as a consequence there has been a relative paucity - by comparison - of data in women. Data from a number of studies have been conflicting, with some showing that plasma HIV RNA levels are lower in women at equivalent CD4+ T-cell levels to those in men (39,105-107,111,125,134,149). Although this may be the case early in the course of infection, the differences dissipate over time such that at 5-6 years, there are no gender differences (157,158). Moreover, rates of clinical progression are equivalent (158). Hence there are no gender differences in the current treatment recommendations. There is little evidence to suggest that the immunological and virological response to ART is affected by ethnicity. However, patients from minority ethnicities in developed world countries may do less well for social and cultural reasons - including not having been tested for HIV infection - and as a consequence presenting late in the course of HIV infection with or without an active AIDS defining illness (17,72,119,141).

There is a paucity of long-term data on genotypic resistance and treatment outcomes for many of the non-clade B viruses and new recombinant viruses. The dominant clades globally are A and C, however, current NRTI and protease inhibitors have been developed using sequences of clade B reverse transcriptase and protease enzymes due to the predominance of clade B HIV-1 virus in the developed world (80). Until more definitive information on the long term effects of this genetic diversity on treatment outcomes becomes available, initiation of ART for non-clade B virus should follow the same guidelines as for clade B virus with the caveat that there may be relatively few antiretroviral drugs available where non-clade B viruses predominate anyway.

Strategies such as “induction-maintenance”, structured treatment interruption (reviewed in (118)), the adjunctive use of immunotherapy to augment responses to ART (46) have been subject to clinical research over many years. The rationale for exploration of induction-maintenance and structured treatment interruption strategies has been to explore whether HIV patients could maintain good health whilst simplify dosing regimens, reducing the risk of chronic toxicity by reduced drug exposure and preserve future drug options. Cost has also been a factor in the developing world. Recently, two separate, randomized clinical trials of intentional, CD4+ T-cell count-guided treatment interruption have been reported. The first of these, the SMART study (161) is described in more detail above; the study clearly demonstrated a deleterious clinical impact of ART cessation compared to continuous ART. The second, the TRIVACAN study (36), which used the same CD4+ count triggers for stopping and restarting treatment as in SMART, also showed that interruption was an inferior strategy compared to continuous ART. Both studies were stopped early following the recommendations of their respective Data Safety and Monitoring Boards. Further analyses are ongoing to better understand the pathogenesis underlying these findings. In contrast, several smaller studies of structured treatment interruption have not shown any deleterious effects, this may been a consequence of smaller numbers and shorter duration (i.e. underpowered to detect a clinical difference) or different design (i.e. different restart thresholds etc) (4,22,91). Induction-maintenance strategies and single class treatment (using PI) for treatment of HIV-infection are the subject on ongoing research (5,20,21). However, new combinations are achieving rates of undetectable virus around the 80% level at 48 weeks (at least in the trial setting). Hence, it is being increasingly more difficult to accept rates of 50-60% undetectable over the same time frame as being representative of “success”.

While there are a much larger number of drugs in the existing armamentarium for use in the treatment of HIV infection, all have their pros and cons. In choosing an antiretroviral combination for first-line treatment of HIV, clinicians should have a strategic plan as to what they will use as a second, third, and even fourth line ART when viral failure and/or toxicity necessitating a switch occurs. HIV infection should be considered a chronic, treatable illness and so, in approaching ART in antiretroviral naïve patients, the ART should be individualized as much as possible, whilst using the guidelines, in order to maximize the chances of long-term success.

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